Physico-chemical and pharmacological properties of the lead

substances and drug development

PHR 222.1

Assigned by: Submitted by

Dr. Borhan Uddin
Melita mehjabin
2011159649
Shamama Siddiqua
2011196049
 Table of Content

1. Amlodipine (Calcium-Channel blocker)

2. Captopril (ACE Inhibitor)

3. Metoprolol (Beta-Blocker)
Lead Compound in Drug Discovery
Drug discovery is the process by which new candidate
medications are discovered. Historically, drug
discovery was based on natural products extracted
from plants and animals.

 Chemical compound with pharmacological or biologicalactivity

 May have a suboptimal structure
 Offers the prospect of being followed by backup compounds (analogs)
 Serves as a starting point for chemical modifications
 Amlodipine Metoprolol 1-
3-O-ethyl 5-O-methyl 2- Captopril (propan-2-
(2-aminoethoxymethyl)- (2S)-1-[(2S)-2-methyl-3- ylamino)propan-2-ol
4-(2-chlorophenyl)-6- sulfanylpropanoyl]pyrrolidine-2- substituted by a 4-(2-
methyl-1,4- carboxylic acid methoxyethyl)phenoxy
dihydropyridine-3,5- group at position 1
dicarboxylate
Amlodipine (C20H25ClN2O5)
Substituted dialkyl 1,4-dihydropyridine-3,5-dicarboxylate
derivative
Used for the treatment of hypertension, chronic stable
angina and confirmed or suspected vasospastic angina
Works as an antihypertensive agent, a calcium channel
blocker and a vasodilator agent
A dihydropyridine, a member of monochlorobenzenes,
an ethyl ester, a methyl ester and a primary amino
compound.
Mechanism of action
Pharmacological Properties
Drug class Calcium Channel Blocker
Onset of action Highest availability 6-12 hours
Duration of action At least 24 hours
Solubility DMSO (25mg/mL), Soluble in methanol, 100% ethanol
(25mg/mL),
dimethyl formamide (25mg/mL) or chloroform
Absorption Slowly & almost completely absorbed from GIT. Peak
plasma concentration achieved after 6-12 hours of oral
administration
Physical Properties
Physical state White round tablet imprinted “U”
Molecular weight 408.879g/mol

Form Solid
Melting Point 199-201°C
Boiling point 527.2±50.0°C
Storage temperature 2-8°C

Chemical Properties
Elimination half- 30-50 hours
life
pKa 8.6
Puriety ≥98% (Assay)
Protein binding About 98%
Bioavailability 64-90%
DOSE
Hypertension
FDA Dosage
 Initial dosage: 5mg orally once a day
 Maximum dosage: 10mg once daily
Guideline dosage Adverse Effects
•Cardiovascular: Edema (1.8% -
 Initial dosage: 2.5 mg orally once 10.8%)
 Target dosage: 10 mg once daily •Gastrointestinal: Abdominal pain
(1.6%)
•Nausea: (2.9%)
•Neurologic: Somnolence (1.4%)
•Other: Fatigue (4.5%)
•Palpitations: (4.5%)
Stable angina, Chronic
Usual dosage: 5 - 10mg orally once a day, most
patients require 10mg for adequate effect.

Variant angina
Usual dosage: 5-10mg orally once daily;
most patients required 10mg dose in the
clinical trial.
Side effects
•Headaches
•Dizziness
•Flushing
•Pounding heartbeat
•Swollen ankles
Contradictions
 
Known hypersensitivity to the drug or its components
Sick sinus syndrome (except in patients with an
artificial pacemaker)
Severe hypotension
Acute myocardial infarction
Pulmonary congestion
Captopril
Captopril is a potent, competitive inhibitor of angiotensin-
converting enzyme (ACE), the enzyme responsible for the
conversion of angiotensin I (ATI) to angiotensin II (ATII).
ATII regulates blood pressure and is a key component of
the renin-angiotensin-aldosterone system (RAAS).  
Captopril is an ACE inhibitor which is used for the
management of essential or renovascular hypertension,
congestive heart failure, left ventricular dysfunction
following myocardial infarction, and nephropathy.
Pharmacological Properties
Drug class ACE Inhibitor
Onset of action Effective within 15-20 minutes

Duration of action Maximum 60-90 minutes

Solubility Freely soluble, at >100 mg/ml in water, methanol,
ethanol, isopropanol, chloroform, or methylene
chloride
Absorption 60-75% in fasting individuals; food decreases
absorption by 25-40% (some evidence indicates
that this is not clinically significant)

Physical–Chemical Properties
Captopril is a white crystalline powder having a characteristic sulfide-like odor and
a melting point between 105 and 108°C. It is freely soluble in water or diluted
solutions of alkali hydroxides, in alcohols, in methylene chloride, or in chloroform.
Metoprolol: C15 H25 NO3
Metoprolol is a beta-blocker used in the treatment of
hypertension and angina, and used to reduce mortality
due to myocardial infarction.

Physicochemical Properties: Pharmacological properties:

1) Molecular weight (267.36)
2)melting point (120 °C)
3)boiling point (398ºC estimate)
4)vapor point
5)molecular polarity
Drug Class: Beta Blockers
Maintenance dose: 100 mg orally twice
a day.
Duration of action: Maximum 60-90
mins
Conclusion
Physical changes do not produce a new
substance. Chemical changes result in the
production of a new substance and cannot
be reversed.