Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550

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Bioorganic & Medicinal Chemistry Letters

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Digest

Applications of amide isosteres in medicinal chemistry T

a,⁎ a b
Shaoyi Sun , Qi Jia , Zaihui Zhang
a
Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada
b
Signalchem Lifesciences Corp., 110-13210, Vanier Place, Richmond, BC V6V 2J2, Canada

ARTICLE INFO ABSTRACT

Keywords: Isosteric replacement of amide groups is a classic practice in medicinal chemistry. This digest highlights the
Amide isostere applications of most commonly employed amide isosteres in drug design aiming at improving potency and
Transition-state mimic selectivity, optimizing physicochemical and pharmacokinetic properties, eliminating or modifying toxicophores,
Heterocycle as well as providing novel intellectual property of lead compounds.
Trifluoroethylamine
Fluoroalkene
3-Aminooxetane
Boronic acid

Introduction the use of TS mimics as non-hydrolysable amide isosteres to replace a

Peptides and nonpeptidic small-molecule amides represent an im-
portant class of biologically active molecules. The potential use of these
molecules as oral drugs is often compromised by their poor physico-
chemical (PC) and pharmacokinetic (PK) properties, largely due to the
metabolic instability of the amide bond toward enzymatic degradation
and/or the high polarity. Therefore, isosteric replacement of the amide
group has been widely adopted as a fundamental tactical approach in
medicinal chemistry for the design of new drugs.1 The success of this
strategy in identifying new biologically active molecules in distinct
therapeutic areas has gained a significant growth. This digest highlights
most commonly employed amide isosteres in drug design and in-
corporates sufficient details in addressing a number of aspects relative
to the amide groups, including the importance in improving potency
and selectivity, optimizing PC and PK properties, eliminating or mod-
ifying toxicophores, as well as providing novel intellectual property of
lead compounds. Representative examples selected in this digest are
classified into six categories: transition-state (TS) mimics, heterocycles,
trifluoroethylamine, fluoroalkene, 3-aminooxetane, and boronic acid.
By summarizing these examples, we hope to provide medicinal che-
mists an overview of the usefulness of these amide isosteres in drug
design.
Transition-state mimics as peptide bond isosteres
Chemical modification of peptides to improve their biological ac-
tivity and PC-PK properties has been extensively studied.2 In particular,
specific scissile peptide bond is a well-known approach to overcome
one of the major drawbacks in the use of peptides as medical agents,
namely, their rapid degradation by peptidases.3 A TS mimic is defined
as a functional group that can mimic the tetrahedral TS of amide bond
hydrolysis, but cannot itself be hydrolyzed by the enzyme. Some TS
mimics that have been successfully used in the design of protease in-
hibitors are depicted in Fig. 1.
Saquinavir (1, Fig. 2) is the first TS peptidomimetic to be approved
by the FDA for the treatment of AIDS.4 The design strategy applied by
the Roche team was to focus on the HIV pol substrate fragment Leu165-
Ile169, which contains the scissile bond Phe167-Pro168. Optimization
of this peptide was achieved by applying the hydroxyethylamine (I,
Fig. 1) TS mimic.
Following the discovery of saquinavir, seven other analogs have
been successfully marketed for medical use including nelfinavir (2),5
amprenavir (3),6 indinavir (4),7 ritonavir (5),8 lopinavir (6),9 darunavir
(7),10 and atazanavir (8),11 which exhibited better potency and/or PK
properties than saquinavir. Atazanavir (8, Fig. 2) contains a hydro-
xyethyl hydrazine fragment (VI, Fig. 1). The aza modification elimi-
nated one of the chiral centers in the molecule, thereby reduced the
challenges associated with the synthesis of this compound.
Aliskiren (11, Fig. 3) represents a unique class of peptidomimetic
renin inhibitors, developed by Novartis for treatment of hypertension.
The design of aliskiren was focused on the modification of the large
peptide CG29287 (9) derived from the N-terminal sequence of angio-
tensinogen by incorporation of the statine TS mimic (V, Fig. 1) at the
renin cleavage site. Subsequent reduction of molecular size by

⁎
Corresponding author.
E-mail address: ssun@xenon-pharma.com (S. Sun).

https://doi.org/10.1016/j.bmcl.2019.07.033
Received 26 April 2019; Received in revised form 17 July 2019; Accepted 19 July 2019
Available online 22 July 2019
0960-894X/ © 2019 Elsevier Ltd. All rights reserved.
S. Sun, et al.
Figure 1. Selected transition-state (TS) mimics.
truncation at both the N- and the C-terminus and incorporation of a
hydroxyethylene isostere (II, Fig. 1) led to CGP38560 (10), and further
structure refinement afforded the drug molecule 11.12
TS mimics (Fig. 1) have also been utilized in the design of less
peptide-like β-secretase (BACE-1) inhibitors.13 This approach produced
many potent inhibitors containing statine (e.g., compound 12),13b hy-
droxyethylene (e.g., compound 13),13c reduced amide (e.g., compound
14),13m and hydroxyethylamine (e.g., compound 15)13n cores (Fig. 4).
Compound 15 is the latest brain penetrant molecule in this class re-
ported by Bueno et al. with a brain to plasma ratio of 0.38 in mice.
Unlike HIV protease and renin, BACE1 is a CNS located aspartic pro-
tease, and despite extensive efforts that have been made, none of these
compounds was selected for clinical development, largely due to the
challenges to achieve optimal CNS penetration. However, information
gathered in these studies can be applied to the optimization of mole-
cules of peripheral targets.
Heterocycles as amide bond surrogates
Replacement of an amide group with a heterocyclic ring in a
bioactive molecule can have many important effects on physicochem-
ical and pharmacological properties.1 This substitution introduces
structural rigidity, which may lead to compounds with improved po-
tency, selectivity, metabolic stability, and PK properties. Commonly
used heterocycles include triazoles, imidazoles, oxadiazoles, oxazoles,
isoxazoles, imidazolidinones, triazolones and many six-membered het-
erocycles, which retain the geometry of the amide bond or maintain the
hydrogen bond (H-bond) accepting/donating properties of the amide
group, and yield many successful examples.
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Diazepam (16, Fig. 5), an agent increases the activity of the GABA
neurotransmitter in the brain, was marketed by Hoffmann-La Roche for
treatment of a number of CNS disorders such as anxiety, epilepsy,
muscle spasms and alcohol withdrawal syndrome.14
In humans, demethylation of diazepam is effected by CYP450 en-
zymes (CYP 2C9, 2C19, 3A4, 3A5, and 2B6), producing the active
metabolite desmethyldiazepam (structure not shown),15 which is
equipotent to diazepam.16 Due to its longer half-life (50–120 h), des-
methyldiazepam accumulates in humans as a major active component
during administration.17
An extensive investigation of amide isosteres derived from dia-
zepam at Upjohn resulted in the discovery of alprazolam (17), a ben-
zodiazepine with a 1,2,4-triazole ring fused to its structure. Alprazolam
is a highly potent, short-acting benzodiazepine, which was approved as
an anxiolytic drug in 1983.18
Midazolam (18) is another diazepam analog, in which the amide
was modified into a imidazole ring, and is an agent used for anesthesia,
seizure suppression, procedural sedation, trouble sleeping, and severe
agitation.19
In an effort to develop more potent calcitonin gene-related peptide
(CGRP) receptor antagonists for treatment of migraine, Merck re-
searchers explored fused heterocyclic derivatives of their clinical can-
didate telcagepant (19, Fig. 6). The imidazoazepane scaffold (as shown
in structure 20) was identified as a suitable replacement for the lactam.
This investigation led to the identification of MK-2918 (21) as a novel
and highly potent CGRP receptor antagonist. Compound 21 contains an
azabenzoxazinone spiropiperidine fragment, which improved the PK
properties in rhesus monkeys. The tertiary methyl ether element at-
tached on the imidazole ring greatly enhanced the potency and
S. Sun, et al.
Figure 2. Structures of peptide-derived TS inhibitors of HIV protease.
diminished the hERG activity.20
In a similar approach, Elliott et al. replaced the lactam present in
compound 22 (Fig. 7) with heterocycles leading to a series of novel
human neurokinin-1 receptor (hNK1R) antagonists. Both triazolone
(23) and imidazole (24) displayed similar potency to that of 22.
However, these two compounds showed different profiles; triazolone 23
demonstrated good activities in a gerbil in vivo model and low hIkr af-
finity, while imidazole 24 was inactive in this in vivo model and showed
insufficient selectivity over hIkr.21
1,2,4-Oxadiazole and 1,3,4-oxadiazole heterocyclic systems have
both planarity and dipole moment similar to the amide functionality,
however, they lack the H-bond donating capacity. Replacement of an
amide group with an oxadiazole can lead to improvements in metabolic
stability, membrane permeability and CNS penetration 22
An example worthy of note is given by the γ-secretase inhibitor 25
(Fig. 8), a compound poorly stable in both rat and human microsomal
incubation. Oral administration of 25 in rats revealed that the brain to
plasma ratio was very low (0.01). In an effort to improve metabolic
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Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550
stability and brain penetration, the benzamide functionality was re-
placed with an 1,2,4-oxadiazole ring and the isobutyl side chain was
modified to a trifluoropropane group. These modifications identified
BMS-708163 (26), a potent, selective, metabolically stable, and orally
bioavailable γ-secretase inhibitor with IC50 values of 0.3 nM and
0.27 nM in reduction of Aβ40 and Aβ42. BMS-708163 demonstrated
favorable PK properties in both rats and dogs, and the brain to plasma
ratio in dogs reached 2.4. BMS-708163 has been evaluated in clinical
trials as a potential treatment of Alzheimer's disease.23
A recent example where an amide bond was replaced with ox-
adizaoles was reported in the optimization of a subtype selective me-
tabotropic glutamate receptor subtype 7 (mGlu7) negative allosteric
modulator (NAM) 27 (Fig. 9).24a While compound 27 displayed good in
vitro activity, its poor metabolic stability (rat CLp = 64.2 mL/min/kg)
limited the in vivo evaluation. Reed et al. found that both 1,2,4- and
1,3,4-oxadizaole rings are effective bioisosteres of the amide bond in
27. In combination with a replacement of the triazole substitution with
an imidazole ring, this modification led to the most potent mGlu7 NAM
S. Sun, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550

Figure 3. Structures of renin inhibitors 9, 10 and aliskren (11).

28 (VU6019278) in this series, which showed low predicted hepatic

clearance (rat CLhep = 27.7 mL/min/kg) and high CNS penetration (rat
Kp = 4.9, Kp,uu = 0.65).24b
The discovery of the human immunodeficiency virus type-1 (HIV-1)
integrase inhibitor raltegravir (36) illustrated the role of 1,3,4-ox-
adiazole as an effective amide isostere in modulating potency shift in
cell based antiviral assays in a medium containing 10% heat-inactivated
fetal bovine serum (FBS) or 50% normal human serum (NHS).25 As
summarized in Fig. 10, 2-pyridine carboxamide 30 was 2-fold less ac-
tive on the enzyme than 29, with a 6-fold shift in cell based assay in the
presence of 10% FBS, but a 50-fold shift in the presence of 50% NHS.
Figure 5. Structures of diazepam (16), alprazolam (17) and midazolam (18).
Addition of more nitrogen in the ring reduced the potency shift, e.g.,
pyrimidine derivative 31 was potent in all assays, while only a marginal
improvement was observed with pyridazine derivative 32. The five-

Figure 4. Structures of BACE-1 inhibitors 12–15.

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S. Sun, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550

Figure 6. Structures of telcagepant (19), compound 20 and MK-2918 (21).

membered analogs oxazole 33, imidazole 34, thiazole 35 and triazole

37 showed single-digit nanomolar activity on integrase, however, a
large potency decrease was observed in cellular assays in both 10% FBS
and 50% NHS conditions for all four analogs. Oxadiazole 36 was the
most potent compound with minimal potency shift in cell based anti-
viral assays. The good potency, selectivity, mutants, PK and safety
profiles of 36 contributed to its success in clinical development as the
first HIV-integrase inhibitor approved for the treatment of HIV-1 in-
fection in the United States in 2007.
In the case of γ-secretase inhibitor 38, replacement of the amide
bond with oxadiazoles resulted in a significant improvement in CYP3A4
liability. As shown in Fig. 11, oxadiazoles 39 and 40 maintained similar
γ-secretase inhibition to that of amide 38, along with reductions in Figure 8. Structures of compounds 25 and BMS-708163 (26).
CYP3A4 activity, suggesting that both oxadiazoles were proper amide
isosteres in this particular case. In contrast, a significant increase in analogs, where the amide portion was replaced with a series of five-
CYP3A4 inhibition was observed with oxazole 41.26 membered heterocycles. As shown in Fig. 12, oxadiazole analog 43 and
Initial SAR exploration around phosphoinositide 3-kinase δ (PI3Kδ) oxazole analog 44 showed comparable potency for PI3Kδ to amide 42,
inhibitor 42 and homology docking suggested that an internal H-bond suggesting that the H-bond donor of the amide was not necessary for
in the molecule maintains a planar binding conformation, facilitating the potency. In addition, furan analog 46 was almost equipotent to
an effective interaction of the key Trp760 residue in the biding pocket. compounds 42, 43 and 44, suggesting that the H-bond acceptor was
Building on this hypothesis, Down et al. designed a class of small size also not necessary for the potency, since furan is a weak H-bond

Figure 7. Structures of hNK1R antagonists 22–24.

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Figure 9. Structures of mGlu7 NAM 27 and VU6019278 (28).

acceptor27. In contrast, thiophene analog 47, predicted to have a non-
planar preferred conformation, was about 10-fold less potent relative to
the progenitors, supporting the hypothesis that the planarity of the
amide linker was essential for the potency. Further refinements of ox-
adiazole analog 42 and oxazole analog 44 by addition of extended
amine groups on the oxadiazole and oxazole rings identified clinical
candidate GSK2269557 (45) for the treatment of respiratory indications
via inhalation.28
CDA54 (48) was reported to be a potent and state-dependent so-
dium channel (NaV1.7) blocker. Evaluation of 48 in human liver mi-
crosomes (HLM) showed rapid cleavage of the N-Me amide side chain,
leading to dealkylated metabolites.29a Key SAR studies were executed
toward identification of analogs with improved PK properties by re-
placing this amide group with heterocycles. These efforts led to the
identification of two series of novel NaV1.7 blockers as exemplified by
isoxazoline 4929b and isoxazole 50.29c Both compounds displayed im-
proved PK properties, and in vivo efficacy in rodent pain models similar
to CDA54 (see Fig 13).
In the optimization of ataxia telangiectasia mutated and rad3-re-
lated (ATR) kinase inhibitor VE-821 (51), initial efforts were focused on
replacing the anilide group with a variety of fused heterocycles such as
benzimidazole, benzoxazole, benzothiazole, and indole to address the
potential liability associated with the aniline buried in the molecule.
Although the ATR potency was maintained, these structural changes
resulted in significant decreases in selectivity for ATR against ataxia
telangiectasia mutated (ATM) kinase.30a Homology modeling analyses
suggested that phenyl substituted five-membered heterocycles could
closely mimic the shape of the anilide and fit in the binding pocket

Figure 10. Selected SAR toward raltegravir (36).

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S. Sun, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550

Figure 11. Selected SAR of γ-secretase inhibitor 38

and its heterocyclic analogs.

Figure 12. Key SAR toward PI3Kδ inhibitor GSK2269557 (45).

Figure 13. Structures of NaV1.7 inhibitors 48–50.

properly without causing steric clashes with the tyrosine gatekeeper Subsequently, the more potent isopropylsulfone 52 was taken as a
residue of the phosphoinositol 3-kinase-like kinase (PIKK) family, po- starting point, and a matched pair of 53 and 54 was evaluated. The
tentially retaining the potency and selectivity for ATR over ATM. partially saturated 4,5-dihydroisoxazole analogue 53 was found to be

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S. Sun, et al.
Figure 14. Key SAR toward ATR inhibitor VX-970 (55).
much less active than the flat unsaturated isoxazole 54, suggesting that
a planar heterocyclic linker is necessary for optimal binding with the
enzyme. As summarized by the data in Fig. 14, aromatic five-membered
heterocycles are generally well tolerated as an amide replacement with
many compounds showing similar affinity on ATR to that of amide 52,
and the selectivity for ATR over the homologous kinases ATM and DNA-
dependent protein kinase (DNA-PK) was maintained.
As predicted by the negative relative conformational energies,
compounds 54, 56, 57 and 59 favor the bioactive conformation,
showing low nanomolar potency against ATR. 1,2,4-oxadiazole 58 fa-
vors the alternative conformation, and was the least active compound
among this set of analogs. The preference for the alternative con-
formation of 58 was predicted by the positive relative conformational
energy, and is in agreement with the observation that aromatic nitrogen
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Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550
atoms are better H-bond acceptors than aromatic oxygens. Because of
its good potency and superior selectivity, isoxazole 54 was selected for
exploration of a highly negatively charged area of the ATP biding site
and ultimately led to the discovery of VX-970 (55), the first ATR in-
hibitor evaluated in humans.30b
1,2,3-triazole is among the most common amide bond isosteres; its
structural features allow a good overlap with an amide, and it has better
H-bond accepting and H-bond donating capacity than an amide, how-
ever, it possesses strong dipole moment.31 The 1,4-disubstituted 1,2,3-
triazole analog 60 was examined in this study and found to be less
active in cell-based assay.30b Examples where replacement of amide
bonds with 1,2,3-triazoles had detrimental effects on potency have also
been reported by Doiron et al. in a series of cystic fibrosis transmem-
brane conductance regulator (CFTR) modulators.32
S. Sun, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550

Figure 15. Structures of PPARδ modulators 61 and 62.

Figure 16. Structures of SCD1 inhibitors 63–66.

Figure 17. Structures of GSM modulators 67–69.

An X-ray structure of the PPARδ modulator 61 (Fig. 15) bound to
the ligand binding domain revealed that the amide portion exists in the
thermodynamically disfavored cis-amide orientation.33a This observa-
tion promoted the authors to replace the amide bond with five-mem-
bered heterocycles to secure the bioactive conformation. Among a
number of heterocyclic derivatives evaluated, the imidazole series of
compounds displayed significantly better PPARδ activity and se-
lectivity, e.g., the corresponding imidazole analog of 61 (structure not
shown) had an EC50 of 1 nM for PPARδ with greater than 1200-fold
selectivity over PPARα. The further optimized compound 62 was a
potent and selective PPARδ modulator with good PK properties. Analog
62 altered the expression of PPARδ target genes and improved fatty

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S. Sun, et al.
Figure 18. Key SAR toward HCV NS5A inhibitor daclatasvir (73).
acid oxidation when tested in mice and in patient-derived muscle
myoblasts. These studies support the hypothesis that selective PPARδ
modulators may offer benefits as a therapeutic target for Duchenne
muscular dystrophy.33b
In the quest for novel and potent stearoyl-CoA desaturase-1 (SCD1)
inhibitors, researchers at Xenon and Novartis discovered that replace-
ment of the amide moiety at the C2-position in compound 63 with
heterocycles resulted in substantial improvements in potency and
physicochemical properties. Both imidazolidinone and triazolone rings
revealed to be ideal replacements for the amide group. This modifica-
tion provided a series of novel, potent, and metabolically stable SCD1
Figure 19. Structures of TRPV1 inhibitors 74–76.
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inhibitors, exemplified by 6434a and 65,34b which demonstrated sig-
nificant efficacy in reducing the plasma C16:1/C16:0 triglycerides de-
saturation index in rats. Furthermore, the amide portion at C5-position
in compound 64 was replaced with a 1,2,4-triazole moiety. However,
compound 66 was found to be about 16-fold less active than 64
(Fig. 16).34c
E-2012 (67, Fig. 17) represents a new class of γ-secretase mod-
ulators (GSMs) with impressive potency in reduction of Aβ42 in cells.
The clinical development of 67 was suspended due to the finding of rat
lenticular toxicity. Sun et al. modified the structure of 67, and identified
oxadiazine as an effective replacement of the lactam in 67. The es-
sential design was built on an analysis of related patent literature that
the middle part of the molecule can be highly variable, and a bulky
group was well tolerated at the benzylic position (as shown in 68),
which inspired the team to build a ring system from the position of the
carbonyl oxygen to the benzylic position. An imino group would be able
to form such a ring while still maintaining the H-bond accepting fea-
tures of the carbonyl oxygen. However, it is too basic, thus may lead to
Pgp efflux and hERG liabilities. Therefore, a series of less basic hy-
droxyamidines, including oxadiazolines and oxadiazines, were pre-
pared. Oxadiazine 69 was one of the most potent GSM, which de-
monstrated significant efficacy in reduction of Aβ42 in rats (3 mg/kg,
orally) and cynomolgous monkeys (30 mg/kg, orally). The corre-
sponding plasma exposure of 69 in monkeys was ∼6 μM (4 h post‐-
dosing), and the average brain/plasma ratio was determined to be
1.4.35
In the optimization of a series of hepatitis C virus (HCV) NS5A in-
hibitors with dual GT-1a/-1b inhibitory activity at Bristol-Myers
Squibb, the potential genotoxic issue associated with the aniline present
in compound 70 was addressed by fusing the amide on the phenyl to
form a benzimidazole ring that mimics the H-bond donating and ac-
cepting properties of the amide moiety. Subsequent modification of the
central core of 71 by removal of the alkyne linker and extension of the
benzimidazole ring to a phenyl-imidazolyl fragment effectively restored
the GT-1a inhibitory potency and finally, replacement of the R-phe-
nylglycine fragment in 72 with L-valine along with a chiral inversion
improved PK properties and led to the discovery of daclatasvir (73,
Fig. 18)36 Daclatasvir is the first HCV NS5A replication complex in-
hibitor marketed to treat HCV patients.
Researchers at Merck have identified amide 74 (Fig. 19) as a potent
transient receptor potential vanilloid 1 (TRPV1) antagonist. Evaluation
of 74 in rats (5 mpk) revealed poor oral absorption with low hepatic
portal vein (HPV) and systemic exposures (AUChpv = 0.08 μM h,
AUCsys = 0.04 μM h, respectively). To improve the PK properties of 74,
a number of fused heterocyclic derivatives were examined and yielded
benzimidazoles and indazolones as promising carboxamide isosteres,
which retained good in vitro potency on hTRPV1. While benzimidazole
S. Sun, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550

Figure 20. Structures of TYK2 inhibitors

77–79.

Figure 21. Structures of compounds 80, 81 and BMS-770767 (82).

Figure 22. Structures of p38α MAPK inhibitors 83–85.

Figure 23. Structures of KV1.3 inhibitor 86 and KV1.5 inhibitors 87 and 88.

75 showed a modest improvement in PK (AUChpv = 1.48 μM h,
AUCsys = 1.25 μM h, respectively), indazolone 76 demonstrated a sig-
nificantly enhanced PK profile in rats (AUChpv = 6.2 μM h,
AUCsys = 3.0 μM h, respectively). Compound 76 was also found to have
low plasma clearance of 8 mL/min/kg with a half-life of 3.6 h (iv,
1 mpk).37
In an effort to discover potent and selective tyrosine kinase 2 (TYK2)
inhibitors, Liang et al. investigated structurally restricted analogs de-
rived from lead 77 (Fig. 20), in which the rotatable benzamide bond
was cyclized on the pyridine ring to form fused heterocycles. This
modification led to several active scaffolds including imidazopyridine,
oxazolopyridine, thiazolopyridine, and pyrazolopyridine. Imidazopyr-
idine 78 had an IC50 value of 1.7 nM with much better selectivity over
Janus kinase 2 (JAK2). Optimization of 78 was carried out by replacing

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S. Sun, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550

Figure 24. Structures of CHK1 inhibitor 89–91.

Figure 25. Structures of HLE inhibitors 92–94.

JAK2, and demonstrated efficacy in an imiquimod-induced psoriasis

Figure 26. Structures of PLG 95 and PLG-mimetic 96.
the cyclopropyl amide portion with an amino pyrimidine group, and
consecutively appending a cyano group on the dichlorophenyl ring to
improve PK property. Compound 79 potently inhibited the TYK2 en-
zyme and the IL-23 pathway in cells, exhibited high selectivity over
model in mice.38
Compound 80 (Fig. 21) was one of the highly potent and selective
inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-
HSD-1) identified by scientists at Bristol-Myers Squibb.39a To discover
structurally distinguished 11β-HSD-1 inhibitors, the team investigated
a number of heterocycles as potential H-bond accepting surrogates to
mimic the amide portion in 80, and identified 1,2,4-triazolopyridine
(shown in compound 81) as an effective replacement of the picolina-
mide core. Optimization of 81 was focused on improving metabolic
stability while maintaining the potency on 11β-HSD-1 and ultimately
produced a series of oxygen-linked 11β-HSD-1 inhibitors, represented
by clinical candidate BMS-770767 (82), which has been evaluated in
humans as a potential treatment of type 2 diabetes.39b,c

Figure 27. Structures of Cat. K inhibitors 97, 98, odanacatib (99) and 100.

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S. Sun, et al.
Figure 28. Structures of ABCE1 inhibitors 101–104.
Phthalazinylbenzamide 83 (Fig. 22) represents a class of potent and
selective inhibitors of p38a mitogen-activated protein kinase (MAPK).
PK studies of 83 in rats revealed a suboptimal profile (Cl = 1.7 L/h/kg,
t½ = 1.4 h).40a A cocrystal structure of 83 with p38a revealed that the
carbonyl oxygen engages the NH of Asp168. Based on this observation,
the carbonyl group in 83 was fused on the phenyl ring to form a ben-
zoisoxazole ring. The nitrogen lone pair of the benzoisoxazole isostere
was projected to mimic the carbonyl H-bonding interaction with Asp
168. Analog 84 was found to maintain good potency and selectivity that
compound 83 had. Optimization of 84 was effected by replacement of
the bottom phenyl substitute with a morpholine ring as well as re-
placement of the cyclopropyl group with a methyl. This effort led to the
discovery of compound 85 with equal potency on p38a and lacking of
CYP3A4 activity. Analog 85 showed better PK properties than 83
(Cl = 1.4 L/h/kg, t½ = 2.8 h) and exhibited efficacy (ED50 = 0.05 mg/
kg) in the rat collagen induced arthritis (CIA) model.40b
Benzamide 86 (Fig. 23) was originally identified as a voltage-gated
potassium channel (KV1.x) inhibitor by Merck.41 The main application
of this class of compounds was to block KV1.3 as potential treatments of
various diseases involving the immune system. Researchers at Bristol-
Myers Squibb elaborated this scaffold utilizing conformational con-
strains and amide isosteres by fusing the amide bond into an amino
heterocyclic ring, while maintaining the H-bond features. These efforts
led to a class of novel, potent, and selective KV1.5 inhibitors, which
were useful for treatment of IKur-associated disorders, including atrial
fibrillation, exemplified by indazole 87 and pseudosaccharin amine
88.42
An X-ray crystal structure of checkpoint 1 kinase (CHK1) inhibitor
89 (Fig. 24) revealed that an internal H-bond between the amide CO
and the urea NH groups constrains the conformation in a six-membered
ring. Accordingly, 89 was rigidified into thienopyridine and thieno-
pyridazine class of inhibitors. It was found that these structurally dis-
tinct analogs, e.g., compounds 90 and 91, maintained comparable in-
hibitory activity on CHK1 with IC50 values of 3 nM and 1 nM,
respectively.43
Six-membered heterocycles pyridone and pyrimidone have been
reported as amide surrogates in the design of a series of non-peptidic
human leukocyte elastase (HLE) inhibitors. With the assistance of a
modeling study that docked inhibitor 92 into the active site of HLE,
Brown et al. employed a substituted pyridone to build a bridge from the
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Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550
a-carbon to the adjacent proline methylene, still maintaining the cri-
tical H-bond interactions with Val-216, and a phenyl substituent on the
pyridine ring retains the hydrophobic interaction with the enzyme.
While compound 93 was highly active in vitro with a Ki of 4.5 nM, it was
not orally active at a dose of 20 mg/kg in an acute hemorrhagic assay,
largely due to its poor physical properties, e.g, low solubility (1.8 μg/
mL in saline). Subsequently, extensive optimization was conducted on
93, and eventually led to a series of orally active pyrimidone analogs.
Compound 94 showed excellent bioavailability in rats (62%) and dogs
(88%), and demonstrated an ED50 of 7.5 mg/kg in the acute hemor-
rhagic model (Fig. 25).44
Applying a similar strategy, Saitton et al. designed a 2,3,4-sub-
stitued pyridine derivative 96 (Fig. 26) by mimicking the naturally
occurring Pro-Leu-Gly-NH2 (PLG) tripeptide 95. The PLG-mimetic 96
was found to be more potent than the natural PLG in enhancing the
maximum response of the dopamine agonist N-propylapomorphine
(NPA) at the human D2 receptor in a cell based assay with a maximum
response of 146% at 10 μM (115% for PLG).45
Trifluoroethylamine as an amide isostere
Replacement of an amide with a trifluoroethylamine group was
originally proposed by Zanda in consideration of both geometry and
electronic effects.46 The electron withdrawing effect of the CF3 group
reduces the basicity of the amine, and the electronegative fluorine atom
has some mimicry of the carbonyl oxygen of the amide. While re-
placement of an amide group with the trifluoroethylamine moiety
eliminates metabolic instability to proteases and amidases, this mod-
ification leads to synthetic complexities due to the introduction of a
chiral center in the molecule.
One successful application of trifluoroethylamine as an amide iso-
stere has been found in the design of cathepsin K (Cat K) inhibitor
odanacatib (99), a compound advanced into phase III clinical evalua-
tion as a potential treatment of osteoporosis in patients.47 As shown in
Fig. 27, the cathepsin K inhibitor 97 was moderately selective for ca-
thepsin K over the related enzyme cathepsin L. Replacement of the
arylamide group in 97 with a trifluoroethylamine element resulted in
98 with enhancements in both potency and selectivity. The finely op-
timized product odanacatib is a non-basic molecule with the fluorinated
valine blocking hydroxylation and the cyclopropyl moiety slowing the
amide hydrolysis.
While the CF3 group provided an ideal balance between potency,
selectivity and metabolic stability, odanacatib is a highly crystalline
molecule with low water solubility, which translates into low oral
bioavailability in preclinical species. To address this liability associated
with odanacatib, the less lipophilic difluoroethylamine analogue 100
(log D7 is about 3 log units lower) was designed with anticipation to
improve the solubility. It was also expected that the increased basicity
(pKa is about one log unit higher) would enable the formation of che-
mically stable salts. As anticipated, compound 100 displayed significant
improvement in oral bioavailability in rats and dogs, and the potency
and selectivity were comparable to odanacatib. However, PK studies in
rats of several chemically stable salts of 100, e.g., hydrochloric acid
salt, sulfuric acid salt, methanesulfonic acid salt, and p-toluenesulfonic
acid salt, showed no advantage over the neutral form.48
The trifluoroethylamine component was also employed in the
Figure 29. Calculated dipole moments of the amide
bond, fluoroalkene, trifluoromethylalkene50 and
chloroalkene51.
S. Sun, et al.
Figure 30. Structures of leu-enkephalin (105) and peptidomimetics (106–109).
Figure 31. Structure of HCV NS5A inhibitor 110.
design of a series of BACE-1 inhibitors, where a methylene linker was
placed between the amino and phenyl group to address an aniline
structural alert present in a class of literature BACE1 inhibitors. The
fundamental design was guided by an X-ray cocrystal structure of a
related analog 101 and the recognition of a non-planar benzylamine
moiety was able to adopt an orientation orthogonal to the plane of the
fluorophenyl P1 ring to optimally engage the carbonyl oxygen of
Gly230 of the enzyme. SAR (see Fig. 28) revealed that the pKa of the
benzylic amine plays an important role in modulating the enzymatic
activity. For example, difluoroethyl analog 103 (pKa of 5.2 for 103 vs
3.8 for 102) was about four-fold less potent than trifluoroethyl analog
102, along with an increase in MDR efflux (Er of 3.1 for 103 vs 1.2 for
102). More basic analogs, e.g, the trifluoroethyl group was replaced
with a 3,3,3-trifluoropropyl (pKa of 6.0) or a cyclopropylmethyl group
(pKa of 6.3), were much less active. The CF3-cyclopropyl group pro-
vided an ideal balance of basicity (pKa of 2.9) and geometry to fill the
binding pocket properly. Although further structural optimization was
Figure 32. Structure of pentapeptide 111 and peptidomimetic 112.
2548
Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550
required to overcome the CYP 2D6 inhibitory liability, compound 104
was 18–fold more potent than 102 and demonstrated efficacy in re-
ducing brain Aβx42 levels in mice.49 This example provided an alter-
native approach to mitigate an aniline structural alert.
Fluoroalkene as an amide isostere
The fluoroalkene moiety is considered more lipophilic than an
amide, which makes it an interesting metabolically stable amide iso-
stere for enhancing membrane permeability. Besides the capability of
mitigating the alkene structural alert, the high electronegative fluorine
atom mimics the carbonyl oxygen of the amide and provides a fluor-
oalkene with a substantial dipole moment (1.4 D) (see Fig. 29). How-
ever, this motif is unable to mimic many important features of an amide
group, e.g., it is neither a good H-bond donor nor a good H-bond ac-
ceptor.
Leu-enkephalin (105, Fig. 30) was a potent δ-opioid receptor ago-
nist, but failed to produce analgesia in vivo due to poor PK properties,
e.g., rapid cleavage of the Tyr1-Gly2 bond by aminopeptidase N in
human plasma (t½ = 0.69 min), and of the Gly3-Phe4 bond by angio-
tensin-converting enzyme at the blood–brain barrier (t½ = 130 min).52
Replacement of the Tyr1-Gly2 amide bond with a fluoroalkene was
reported by Altman and colleagues. Although the effects of activating δ-
and μ-opioid receptors were 60- and 45-fold weaker than 105, analog
106 exhibited excellent stability in rat plasma (76% remaining of 106
at 4 h vs t½ < 5 min for 105) and human plasma (68% remaining of
106 at 4 h vs t½ = 12 min for 105). In contrast, trifluoethylamine de-
rivative 107 (both S and R isomers) had no activity at δ-opioid and μ-
opioid receptors at 10 μM concetration.53
S. Sun, et al.
Figure 33. Structures of leu-enkephalin analogs 113–116.
Figure 34. Structures cefalotin (117) and vaborbactam (118).
3 4
Replacement of the Gly -Phe bond with a fluoroalkene was ac-
complished by Nadon et al. Analog 108 displayed high binding affinity
to δ-opioid receptor, suggesting that a H-bond donor at this site was not
essential, the fluoroalkene isostere and the Gly3-Phe4 amide bond act as
a H-bond acceptor. The weak activity of the olefin 109 further high-
lighted the role of the fluorine atom for effective mimicry of the H-bond
accepting feature of the amide.54
Another example is the fluoroalkene containing analog of dacla-
tasvir 110 (Fig. 31), which exhibited picomolar activity against HCV
genotype 1b replicon. However, 110 was much less active on genotype
1a replicon than daclatasvir (structure 73, Fig. 18), suggesting this
genotype is highly sensitive to structural changes.55
In addition, fluoroalkene has also been applied in the design of di-
peptidyl peptidase IV inhibitors as a strategy to improve chemical and
metabolic stability.56
Waelchli and colleagues found that both a fluoroalkene and a
chloroalkene were effective dipeptide isosteres in a series of human
parathyroid hormone agonists.57 Recently, the chloroalkene structure
was introduced into a cyclic pentapeptide 111 in the design of con-
formationally rigid peptidomimetics. The chloroalkene containing
analog 112 (Fig. 32) showed about 20-fold higher activity against
human dermal fibroblast (HDF) attachment to vitronectin compared to
peptide 111.58
However, since the chlorine atom is less electronegative than a
fluorine (3.16 on the Pauling electronegativity scale compared to 3.98
for F) and chloroalkene is more lipophilic than fluoroalkene (cLog P is
about 0.5 units higher), it is not clear if the chlorine atom could ef-
fectively block the metabolic epoxidation of the alkene.
Wipf has proposed that a trifluoromethyl group is a better electro-
static mimic of the carbonyl oxygen of an amide than the fluorine of
fluoroalkene based on the fact that the dipole moment of tri-
fluoromethylalkene (2.3D) is closer to that of an amide (3.6D) (see
Fig. 29). Despite the attractiveness of this hypothesis, the use of
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Bioorganic & Medicinal Chemistry Letters 29 (2019) 2535–2550
trifluoromethylalkene as an amide isostere appears to be less ex-
plored.59
3-Aminooxetane as an amide isostere
The heterocyclic 3-aminooxetane unit as an amide isostere was in-
dependently conceived by Carreira60 and Shipman.61 Replacement of
amides with this non-hydrolyzable motif could, in principle, led to
metabolically stable mimetics. While the oxetane group is able to re-
duce the basicity of the amine by about 3 pKa units, it is a much weaker
H-bond acceptor than an amide carbonyl group,60a which translates
into suboptimal mimicry of an amide.
Carreira et al. modified the natural leu-enkephalin (105, see Fig. 33)
wherein four amide bonds were successively replaced by the 3-ami-
nooxetane structure.60d In this study, leu-enkephalin was found to ra-
pidly degrade in human serum with a half-life of about 10 min. The 3-
aminooxetane analogs 113 and 114 were stable in human serum,
however, lost binding affinity at the rat δ-opioid receptor. Analog 115
showed a slightly increased half-life of about 15 min with a consider-
able affinity of 157 nM. Analog 116 was about two times more stable
with an affinity comparable to leu-enkephalin (Ki of 9.2 nM for 105 in
this test). In addition, 116 exhibited analgesic activity in an in vivo
mouse assay. These results demonstrated that 3-aminooxetane can be a
valuable replacement of an amide, however, the effect on biological
activity and metabolic stability of replacing an amide bond by the 3-
aminooxetane moiety in a bioactive molecule is highly context depen-
dent.
Boronic acid as an amide replacement
There have been considerable efforts in the design of boronic acid
transition-state inhibitors, utilizing the boronic moiety as a replacement
of the reactive β-lactam ring present in β-lactam antibiotics.62 These
novel inhibitors are anticipated to have fewer resistances because they
are able to inhibit klebsiella pneumoniae carbapenemase (KPC) and
other β-lactamases. The rationale behind these designs relies on the
formation of a reversible covalent adduct between the active site serine
in a carbapenemase and the boronic moiety, which mimics the tetra-
hedral TS during the serine carbapenemase-catalyzed lactam hydro-
lysis.
Vaborbactam (118, Fig. 34) a boron-containing mimic of cefalotin
(117), is a potent inhibitor of serine carbapenemases, particularly, the
KPC-producing strains, with no inhibition of mammalian serine pro-
teases.62e Clinical trials of vaborbactam were conducted in combination
with meropenem by Rempex Pharmaceuticals, and eventually the
combination drug vabomere was approved in 2017 by FDA for treat-
ment of complicated urinary tract infections, including pyelone-
phritis.62g
Conclusion
The design and application of amide isosteres have cultivated suc-
cess toward solving a range of problems in drug discovery. However,
one cannot overestimate the impact that an amide isostere might have
on a bioactive molecule. Isosteres are typically less than exact mimics;
an effective isostere for one specific circumstance might not translate
into another case. The effect on biological activity and /or PK proper-
ties of replacing an amide group with a certain isostere in a bioactive
molecule is highly context dependent, and could be beneficial or de-
leterious, e.g., size, shape, electronic distribution, polarity, lipophili-
city, H-bond and pKa, potentially playing key roles in the interactions
between the ligand and its receptor. While lead optimization is chal-
lenging, often no single method is able to solve every problem. The
examples summarized here provide medicinal chemists with a resource
to solve the issues arising from their optimization of bioactive amides.
S. Sun, et al.
Acknowledgments
We thank Dr. Steven S. Wesolowski, Dr. Christoph M. Dehnhardt
and Dr. James R. Empfield for review of the manuscript. We also ap-
preciate Dr. Peter R. Bernstein and the reviewers for suggestions during
revision of this manuscript.
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