CHAPTER 29 / THYROID FUNCTION AND THYROID DRUGS 957
to be a goitrogen, and phloretin, a dihydrochalocone
with a half maximal inhibitory concentration of 4 mol/L.
O O
CH3 HO OH
OH O of its aliphatic and alicyclic ether derivatives showed no
OH O
Warfarin Phloretin
H 2N SO2
NHC4H9
HN
O 3′- and 5′-positions of the outer ring, and 5) 4′-phenolic
Carbutamide
The ability of oxidation products of 3,4-dihydroxy-
cinnamic acid to prevent the binding of TSH to human
thyroid membranes (54) suggests that other oxygenated
phenols may interfere with thyroid hormone function in
more than one way. Examples of iodinated drugs affect-
ing thyroid function are the antiarrhythmic agent amio-
darone and the radiocontrasting agent iopanoic acid.
All of these compounds interfere with the peripheral
deiodination of T4 and are being tested as adjuncts in the
treatment of hyperthyroidism.
CH3
O C4H9 I
CH3 N I
O CH3
O I
I NH2
Amiodarone Iopanoic acid
The binding of thyroid hormones to plasma carrier
proteins is affected by endogenous agents or by drugs that
can change the concentration of these proteins or com-
pete with thyroid hormones for binding sites. Examples
of the first group are testosterone and related anabolic
agents, which are able to decrease the concentration of T4
binding globulin, and estrogens and related contracep-
tive agents, which are able to increase the concentration
of T4 binding globulin. Salicylates, diphenylhydantoin,
and heparin are members of the large group compet-
ing with thyroid hormones for binding sites. Alterations
in the binding of T3 and T4 are of no large physiologic
consequence, because the steady-state concentrations of
free hormone are rapidly restored by homeostatic mech-
anisms. Knowledge regarding the presence of agents
affecting thyroid hormone binding, however, is impor-
tant for the interpretation of diagnostic tests assessing the
presence of free or total hormone in plasma.
STRUCTURE–ACTIVITY RELATIONSHIPS OF
THYROID ANALOGS
The synthesis and biologic evaluation of a wide variety
of T4 and T3 analogs allowed a significant correlation of
structural features with their relative importance in the
production of hormonal responses. The key findings are
Lemke_Chap29.indd 957
summarized in Table 29.2. In general, only compounds
with the appropriately substituted phenyl-X-phenyl
nucleus (as depicted in the structure at the top of Table
29.2) have shown significant thyroid hormonal activities.
OH Both single ring compounds such as DIT and a variety
T4-like activity in the rat antigoiter test (55), the method
most often used in determining thyromimetic activity
in vivo (56). The SARs are discussed in terms of single
structural variations of T4 in the 1) alanine side chain, 2)
3- and 5-positions of the inner ring, 3) bridging atom, 4)
hydroxyl group.
Aliphatic Side Chain
The naturally occurring hormones are biosynthesized
from l-tyrosine and possess the l-alanine side chain. The
l-isomers of T4 and T3 (compounds 1 and 3 in Table 29.2)
are more active than the d-isomers (compounds 2 and 4 in
Table 29.2). The carboxylate ion and the number of atoms
connecting it to the ring are more important for activity
than is the intact zwitterionic alanine side chain. In the
carboxylate series, the activity is maximum with the two-
carbon acetic acid side chain (compounds 7 and 8) but
decreases with either the shorter formic acid (compounds
5 and 6) or the longer propionic and butyric acid analogs
(compounds 9 to 12). The ethylamine side chain analogs
COOH
I of T4 and T3 (compounds 13 and 14) are less active than
the corresponding carboxylic acid analogs. In addition,
isomers of T3 in which the alanine side chain is transposed
with the 3-iodine or occupies the 2-position were inactive
in the rat antigoiter test (57), indicating a critical location
for the side chain in the 1-position of the inner ring.
Alanine-Bearing Ring
The phenyl ring bearing the alanine side chain, called
the inner ring or a-ring, is substituted with iodine in the
3- and 5-positions in T4 and T3. As shown in Table 29.2,
removal of both iodine atoms from the inner ring to form
3′,5′-T2 (compound 15) or 3′-T1 (compound 16) pro-
duces analogs devoid of T4-like activity, primarily because
of the loss of the perpendicular orientation of diphenyl
ether conformation. Retention of activity observed on
replacement of the 3- and 5-iodine atoms with bromine
(compounds 17 and 18) implies that iodine does not play
a unique role in thyroid hormone activity. Moreover, a
broad range of hormone activity found with halogen-free
analogs (compounds 19 and 20) indicates that a halo-
gen atom is not essential for activity. In contrast to T3,
3′-isopropyl-3,6- dimethyl-l-thyronine (compound 20)
has the capacity to cross the placental membrane and
exerts thyromimetic effects in the fetus after adminis-
tration to the mother. This could prove to be useful in
treating fetal thyroid hormone deficiencies or in stimu-
lating lung development (by stimulating lung to synthe-
size special phospholipids [surfactant], which ensure
sufficient functioning of the infant’s lungs at birth)
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 958 PART III / PHARMACODYNAMIC AGENTS

TABLE 29.2 Structure–Activity Relationships of Thyromimetics

R 5'
R 4' R5 R1

R 3' X
R3
Compound R1 R3 R5 X R3′ R5′ R4′ Antigoiter
Activitya
1. L-T4 L-Ala I I O I I OH 100
2. D-T4 D-Ala I I O I I OH 17
3. L-T3 L-Ala I I O I H OH 550
4. D-T3 D-Ala I I O I H OH 41
5. COOH I I O I I OH 0.1
6. COOH I I O I H OH 0.4
7. CH2COOH I I O I I OH 50
8. CH2COOH I I O I H OH 36
9. (CH2)2COOH I I O I I OH 15
10. (CH2)2COOH I I O I H OH 20
11. (CH2)3COOH I I O I I OH 4
12. (CH2)3COOH I I O I H OH 5
13. (CH2)2NH2 I I O I I OH 0.6
14. (CH2)2NH2 I I O I H OH 6
15. L-Ala H H O I I OH <0.01
16. L-Ala H H O I H OH <0.01
17. DL-Ala Br Br O I H OH 93
18. L-Ala Br Br O iPr H OH 166
19. L-Ala Me Me O Me H OH 3
20. L-Ala Me Me O iPr H OH 20
21. DL-Ala iPr iPr O I H OH 0
22. DL-Ala sBu sBU O I H OH 0
23. DL-Ala I I — I I OH 0
24. DL-Ala I I S I H OH 132
25. DL-Ala I I CH2 I H OH 300
26. L-Ala I I O H H OH 5
27. L-Ala I I O OH H OH 1.5
28. L-Ala I I O NO2 H OH <1
29. DL-Ala I I O F H OH 6
30. L-Ala I I O Cl H OH 27
31. DL-Ala I I O Br H OH 132
32. L-Ala I I O Me H Oh 80
33. L-Ala I I O Et H OH 517
30. L-Ala I I O iPr H OH 786
35. L-Ala I I O nPr H OH 200
36. DL-Ala I I O Phe H OH 11
37. DL-Ala I I O F F OH 2.3
38. L-Ala I I O Cl Cl OH 21
39. L-Ala I I O I H NH2 <1.5
40. DL-Ala I I O I H H >150
41. DL-Ala I I O CH3 H CH3 0
42. L-Ala I I O I H CH3O 225
a
See Ekins (68) and Ahmad et al. (69). In vivo activity in rats relative to L-T4 = 100% or DL-T4 = 100% for goiter prevention.
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 CHAPTER 29 / THYROID FUNCTION AND THYROID DRUGS 959

immediately before premature birth (58). Substitution
in the 3- and 5-positions by alkyl groups significantly
larger and less symmetric than methyl groups, such as
isopropyl and secondary butyl moieties, produces inac-
tive analogs (compounds 21 and 22). These results show
that 3,5-disubstitution by symmetric, lipophilic groups
not exceeding the size of iodine is required for activity.
Bridging Atom
Several analogs have been synthesized in which the
ether oxygen bridge has been removed or replaced by
other atoms. The biphenyl analog of T4 (compound 23
in Table 29.2), formed by removal of the oxygen bridge,
is inactive in the rat antigoiter test. The linear biphenyl
structure is a drastic change from the normal diphenyl
ether conformation found in the naturally occurring
hormones. Replacement of the bridging oxygen atom by
sulfur (compound 24) or by a methylene group (com-
pound 25) produces highly active analogs. This provides
evidence against the Niemann quinoid theory, which
postulates that the ability of a compound to form a quin-
oid structure in the phenolic ring is essential for thyro-
mimetic activity, and emphasizes the importance of the
three-dimensional structure and receptor fit of the hor-
mones. Attempts to prepare amino- and carbonyl-bridged
analogs of T3 and T4 have been unsuccessful (59,60).
Phenolic Ring
The phenolic ring, also called the outer or b-ring, of
the thyronine nucleus is required for hormonal activ-
ity. Variations in 3′- or 3′,5′-substituents on the phenolic
ring have dramatic effects on biologic activity and affin-
ity for the nuclear receptor. The unsubstituted parent
structure of this series T2 (compound 26 in Table 29.2)
possesses low activity. Substitution at the 3′-position by
polar hydroxyl or nitro groups (compounds 27 and 28)
causes a decrease in activity as a consequence of both lowered
lipophilicity and intramolecular hydrogen bonding with the
4′-hydroxyl (61). Conversely, substitution by nonpolar halo-
gen or alkyl groups results in an increase in activity in direct
relation to the bulk and lipophilicity of the substituent—
for example, F < Cl < Br < I (compounds 29 to 31) and CH3
< CH2CH3 < CH(CH3)2 (compounds 32 to 34). Although
a second substituent adjacent to the phenolic hydroxyl
(5′-position) reduces activity in direct proportion to its size.
Phenolic Hydroxyl Group
A weakly ionized phenolic hydroxyl group at the 4′-position
is essential for optimum hormonal activity. Replacement
of the 4′-hydroxyl with an amino group (compound 39
in Table 29.2) results in a substantial decrease in activ-
ity, presumably as a result of the weak hydrogen bond-
ing ability of the latter group. The retention of activity
observed with the 4′-unsubstituted compound (com-
pound 40) provides direct evidence for metabolic
4′-hydroxylation as an activating step. Introduction of a
4′-substituent that cannot mimic the functional role of a
phenolic group, such as a methyl group (compound 41),
and that is not metabolically converted into a functional
residue results in complete loss of hormonal activity. The
thyromimetic activity of the 4′-methyl ether (compound
42) was ascribed to the ready metabolic cleavage to form
an active 4′-hydroxyl analog. The pKa of 4′-phenolic
hydroxyl group is 6.7 for T4 (90% ionized at pH 7.4) and
8.5 for T3 (∼10% ionized). The greater acidity for T4 is
reflective of its stronger affinity for plasma proteins and,
consequently, of its longer plasma half-life.
Conformational Properties of Thyroid Hormones
and Analogs
The importance of the diphenyl ether conformation for
biologic activity was first proposed by Zenker and Jorgensen
(63,64). Through molecular models, they showed that a
perpendicular orientation of the planes of the aromatic
Proximal
5'-position
HO
Distal
3'-position H2N
I
COOH
Blocking group O
2'-position
I
R
HO HO CH3
CH3

3′-isopropylthyronine (compound 34) is the most potent CH3 OR CH3 OR

analog known, being approximately 1.4 times as active as
T3, n-propylthyronine (compound 35) is only about one- 2',3'-Dimethyl-3,5- 2',5'-Dimethyl-3,5-
fourth as active as isopropyl, apparently because of its less diiodothyronine (I) diiodothyronine (III)
compact structure. As the series is further ascended, activ-
ity decreases with a further reduction for the more bulky HO HO I
3′-phenyl substituent (compound 36). Substitution in both
3′- and 5′-positions by the same halogen produces less active
hormones (compounds 37 and 38) than the correspond- OR CH3 OR
ing 3′-monosubstituted analogs (compounds 29 and 30).
The decrease in activity has been explained as resulting 4'-Hydroxy-1'-naphthyl-3,5- 2'-Methyl-3,5,5'-triiodo-
diiodothyronine (II) thyronine (IV)
from the increase in phenolic hydroxyl ionization and the
resulting increase in binding to TBG (the primary carrier FIGURE 29.6 Structures of representative distal and proximal
of thyroid hormones in human plasma) (62). In general, compounds.
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 960 PART III / PHARMACODYNAMIC AGENTS

rings of 3,5-diiodothyronines would be favored to mini-
mize interactions between the bulky 3,5-iodines and the
2′,6′-hydrogens. In this orientation, the 3′- and 5′-posi-
tions of the ring are not conformationally equivalent, and
the 3′-iodine of T3 could be oriented either distal (away
from) or 5′ proximal (closer) to the side chain–bearing
ring (Fig. 29.6). Because the activity of compounds such
as 3′,5′-dimethyl-3,5-diiodothyronine had demonstrated
that alkyl groups could replace the 3′- and 5′-iodine sub-
stituents, model compounds bearing alkyl groups in the
3′-position and alkyl or iodine substituents in the 5′-posi-
tion (in addition to the blocking 2′-methyl group) were
synthesized for biologic evaluation (64).
Biologic evaluation of 2′,3′- and 2′,5′-substituted diiodo-
thyronines (65) revealed that 3′-substitution was favorable
for thyromimetic activity but that 5′-substitution was not. The
structures of representative distal analogs, 2′,3′-dimethyl-
3,5-dl-diiodothyronine (compound I) and O-(4′-hydroxy-
1′-naphthyl)-3,5-dl-diiodotyrosine (compound II), and of
the proximal analogs, 2′,5′-dimethyl-3,5-dl-diiodothyronine
(compound III) and 2′-methyl-3, 5,5′-dl-triiodothyronine
(compound IV), are given in Figure 29.6. The effective-
ness of these compounds in rat antigoiter assay (66) is pre-
sented in Table 29.3. These results clearly indicate that in
2′-blocked analogs, a distal 3′-substitution is favorable for
thyromimetic activity, but a proximal 5′-substitution is not.
In addition to being perpendicular to the inner ring,
the outer phenolic ring can adopt conformations relative
to the alanine side chain, which would be cis or trans. In
other words, the cisoid and transoid conformations result
from the methine group in the alanine side chain being
either cis or trans to the phenolic ring (Fig. 29.7). Although
the bioactive conformation of the alanine side chain in
thyroid hormone analogs has not yet been defined, these
conformations appear to be similar in energy, because
both are found in thyroactive structures as determined
by x-ray crystallography (67). The synthesis of confor-
mationally fixed cyclic or unsaturated analogs may allow
evaluation of the bioactivity of the two conformers.
Transthyretin Receptor Model
An additional tool in structural analysis and analog design
has been TTR. TTR is a serum and cerebrospinal fluid car-
rier of T4 and retinol. This is how transthyretin gained its
TABLE 29.3 Effectiveness of Distal and Proximal
Compounds Antigoiter Assay
Compounda Dose (mg/kg/day) % T4 activity
I 0.025 50
II 0.013 >100
III 2.3 <1
IV 0.5 2
a
See text for specific descriptions of compounds I to IV.
name—transports thyroxine and retinol. TTR was origi-
nally called prealbumin because it ran faster than albumins
on electrophoresis gels. TTR, a plasma protein, binds as
much as 27% of plasma T3 (68). The amino acid sequence
of the TTR-T3 binding site is known, and the protein
has therefore served as a model, although admittedly an
approximate model, for the T3 receptor. The TTR model
portrays the T3 molecule as placed in an envelope near
the axis of symmetry of the TTR dimer. In this envelope,
hydrophobic residues, such as those of leucine, lysine, and
alanine, are near pockets accommodating the 3,5,3′- and
5′-positions of T3, whereas the hydrophilic groups of serine
and threonine (hydrogen bonded to water), are between
the 3′-substituent and the 4′-phenolic group. Taking this
model into account, Ahmad et al. (69) suggested that
3′-acetyl-3,5-diiodothyronine might be a good analog or a
good inhibitor of T3, because the carbonyl group of the 3′
acetyl substituent would form a strong hydrogen bond with
the 4′ phenolic hydrogen, thereby preventing its bonding
with the hydrated residue of the putative receptor.
H
O
H
CH3
O
diiodotyrosyl
TBPA-CH 2 O H
O O
H
This compound, prepared by Benson et al. (70), was
found to be indistinguishable from T3 in oxygen uptake
and glycerophosphate activity tests and to be half as
active as T3 in displacing labeled T3 from rat liver nuclei
in specific in vivo conditions.

HO HO
NH3
I I H
COO
O O
COO
I H I
NH3

Transoid conformation Cisoid conformation

FIGURE 29.7 Side-chain conformations of thyroid hormones: transoid (left) and cisoid (right).
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