IPS ORGMED

Organic Pharmaceutical Chemistry

Organic Medicinal Chemistry

An interdisciplinary science concerned with the discovery, design, identification, preparation, and optimization of biologically active compounds for therapeutic use.

Medicinal Chemistry

how molecular structure influences what a drug does in the body.

3D arrangement can affect:

• Receptor binding

• Potency

• Selectivity

• Metabolism

• Therapeutic effects

HIT

Compound showing biological activity

LEAD

Promising compound suitable for further optimization

OPTIMIZATION

Modify structure to improve potency, selectivity, PK, and safety.

CANDIDATE

Selected for further preclinical/clinical development.

Process of Drug Discovery

DESIGN → SYNTHESIZE → MODIFY → EVALUATE → OPTIMIZE

Passive Diffusion

• Most common mechanism for many small molecules.

• Favors nonionized, lipid-soluble drug

• Driven by concentration gradient

• No carrier or ATP required

Facilitated / Active Transport

• Carrier-mediated movement can be selective and saturable.

• SLC transporters: uptake/facilitation

• ABC transporters: often efflux

• Transporters can affect absorption and disposition

Tablets / Capsules

must release drug before absorption can occur.

Dissolution

often the rate-limiting step for poorly soluble drugs

Particle size reduction

usually increases surface area and can increase dissolution rate.

Formulation factors

disintegrants, binders, coatings, crystal form, and salt selection—can change liberation

TRUE

No dissolution → no meaningful absorption of a conventional solid oral dose

Noyes–Whitney Equation

Rate ∝ D × A × (Cs − C) / h

Dissolution Rate increases with

• Greater surface area

• Greater concentration gradient

• Better wetting

• Higher apparent solubility

Micronization

→ ↑ surface area → faster dissolution (if other factors are unchanged).

Poor aqueous solubility

→ dissolution-limited absorption is possible.

Agitation and GI motility

can influence the diffusion boundary layer.

Weak Acid

HA ⇌ H⁺ + A⁻

Weak Base

BH⁺ ⇌ H⁺ + B

Henderson–Hasselbalch

Weak acid: pH = pKa + log(A⁻/HA) | Weak base: pH = pKa + log(B/BH⁺)

Lipophilicity

Greater lipid affinity generally favors membrane partitioning.

• LogP: neutral species

• LogD: distribution at a specified pH; includes ionization

very high lipophilicity may cause:

• Poor aqueous solubility

• High protein/tissue binding

• Greater distribution and sometimes slower clearance

smaller molecules

generally cross lipid barriers more readily than very large molecules.

large biologics

usually require specialized transport, parenteral routes, or other delivery strategies.

more h-bond donors/acceptors

can increase aqueous interactions but may reduce passive membrane permeability when excessive. Balance is key.

Amorphous forms

often have higher apparent solubility than highly ordered crystalline forms, but may be less physically stable.

Salt formation

can improve dissolution or alter stability by changing ionization and solid-state properties.

Polymorphs

are chemically identical but differ in crystal packing; this can change pharmaceutical performance

BIOAVAILABILITY (F)

• Fraction of an administered dose that reaches systemic circulation unchanged.

• IV administration is the reference: F ≈ 1.

Factors lowering F

• Incomplete absorption

• intestinal metabolism/efflux

• hepatic first-pass metabolism

• degradation in GI tract

Factors affecting Oral Absorption

• Drug: pKa, solubility, lipophilicity, particle size

• Formulation: Disintegration, dissolution, excipients, coating

• Patient: GI pH, motility, disease, age

• Food: Changes pH, gastric emptying, bile, binding, enzymes

• Transporters: Uptake and efflux can alter exposure

• First Pass: Intestinal + hepatic metabolism can reduce F

Albumin

commonly binds acidic and many neutral drugs.

α1-acid glycoprotein

commonly binds basic drugs.

TRUE

High binding ≠ automatically high toxicity. Clinical impact depends on changes in free concentration, distribution, clearance, and therapeutic index.

LOW Vd

Drug remains largely in plasma/intravascular space. Often associated with high plasma protein binding and/or large size.

HIGH Vd

Drug extensively distributes into tissues. Often associated with high lipophilicity, tissue binding, or low plasma binding.

Volume of Distribution (Vd)

Vd = amount of drug in body ÷ plasma drug concentration

Loading dose concept:

LD ∝ Vd × target concentration / F

BLOOD–BRAIN BARRIER

Tight junctions + lipid membrane + transporters limit entry. Lipophilic, nonionized molecules generally penetrate more readily.

PLACENTA

Not an absolute barrier. Molecular size, lipophilicity, ionization, protein binding, and transporters influence fetal exposure.

ADIPOSE / TISSUE

Lipophilic drugs may accumulate in tissues and have prolonged apparent half-life.

Phase 1: Functionalization Reactions

• Oxidation

• Reduction

• Hydrolysis

OXIDATION

Introduces/exposes polar functionality; often CYP-mediated

REDUCTION

Adds hydrogen or reduces functional groups; important for some carbonyl, nitro, azo groups.

HYDROLYSIS

Cleaves ester, amide, or related bonds using hydrolases.

Phase 1

• can terminate activity, reduce activity, preserve activity, or create an active metabolite.

• can also create a functional group that becomes a handle for Phase 2 conjugation.

Oxidation Reaction includes:

hydroxylation, dealkylation, deamination, epoxidation, and heteroatom oxidation.

CYP3A is a major contributor to drug metabolism, but not every CYP substrate is a CYP3A substrate

reduction

• Often favored under relatively lowoxygen conditions.

• Examples of functional groups: nitro, azo, carbonyl, disulfide.

• May occur via reductases and other enzymes

hydrolysis

• Common with esters and amides.

• Many ester prodrugs rely on hydrolysis for activation.

• Esterases and amidases can cleave bonds using water.

Phase 2: Conjugation Reactions

• Glucuronidation

• Sulfation

• Acetylation

• Methylation

• Glutathione

• Amino Acid

GLUCURONIDATION

UGT enzymes; UDPglucuronic acid donor

SULFATION

SULT enzymes; PAPS donor

ACETYLATION

NAT enzymes; acetyl-CoA donor

METHYLATION

Methyltransferases; SAM donor

GLUTATHIONE

GST enzymes; glutathione conjugation

AMINO ACID

Conjugation with amino acids for selected substrates

Conjugation

usually increases polarity and promotes elimination.

glucuronidation

a major pathway for many drugs and endogenous compounds, but route and extent vary by substrate.

PRODRUG

A metabolite may be the active species; metabolism can be required for therapeutic effect.

BIOACTIVATION

Metabolism can generate a reactive intermediate that contributes to toxicity.

CYP1A2

Examples: caffeine, theophylline, clozapine. High-yield inducer: smoking (polycyclic aromatic hydrocarbons)

CYP2D6

Clinically important for many antidepressants, antipsychotics, opioids, and beta blockers. Genetic variability is substantial.

CYP3A

Major pathway for many drugs. Important inhibitors: clarithromycin, itraconazole; inducer examples: rifampin, carbamazepine, phenytoin.

Enzyme Induction:

↑ Enzyme Expression → Faster Metabolism

Induction

usually develops over days because new enzyme must be synthesized

typical consequence for an active parent drug?

↓ concentration and ↓ effect

CLASSIC INDUCERS

Rifampin • carbamazepine • phenytoin • phenobarbital • St. John’s wort

CLASSIC INHIBITORS

Clarithromycin • itraconazole • fluoxetine/paroxetine • fluvoxamine • fluconazole

Inhibition

can be rapid because it does not require new enzyme synthesis

competitive inhibiton

often concentration-dependent and reversible.

Time-dependent or mechanism-based inhibition

can persist after the inhibitor is removed because enzyme activity must recover.

Rifampin/ Rifampicin

Strong CYP3A; also induces CYP2C19; affects several other pathways

Carbamazepine

Strong CYP3A inducer; also induces other enzymes

Phenytoin

Strong CYP3A inducer; induces several CYP pathways

Phenobarbital

Broad enzyme induction; classic board example

St. John’s wort

Clinically relevant CYP3A/P-gp induction

Clarithromycin / itraconazole

Strong CYP3A inhibition

Fluoxetine / paroxetine

Strong CYP2D6 inhibition

Fluvoxamine

Strong CYP1A2 and CYP2C19 inhibition; additional effects

Fluconazole

Strong CYP2C19; moderate CYP2C9/CYP3A effects

Gemfibrozil

Strong CYP2C8 inhibition; also transporter effects

Adrenergic Neurotransmission

TYROSINE → L-DOPA → DOPAMINE → NE → EPI

Tyrosine hydroxylase (TH)

rate-limiting

Cocaine

blocks NET; TCAs inhibit NET/other monoamine transporters;

COMT

inhibitors prolong catecholamine action.

Cholinergic Neurotransmission

CHOLINE + Acetyl-CoA —ChAT→ ACh

AChE inhibitors

increase ACh at both muscarinic and nicotinic sites.

MAO

• Mitochondrial enzyme.

• Oxidative deamination.

• Important in neuronal and peripheral catecholamine metabolism.

COMT

• Methylates the catechol ring.

• Important in peripheral metabolism.

• High-yield clue: catechol + methylation → COMT

SYNTHESIS:

Choline + Acetyl-CoA —ChAT→ ACh

STORAGE:

VAChT loads ACh into vesicles

RELEASE:

Ca²⁺-dependent exocytosis

TERMINATION:

AChE hydrolysis

organophosphates

inhibit AChE for prolonged periods; aging of phosphorylated enzyme can make reactivation difficult.

CATECHOL

→ COMT susceptibility + polarity

α-METHYL

→ greater MAO resistance in selected sympathomimetics.