DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 3: Sections 10.3.1 – 10.3.7

Contents Part 3: Sections 10.3.1 – 10.3.7 4. Drug Design - Optimising Binding Interactions 4.1. Vary Alkyl Substituents (20 slides) 4.2. Vary Aryl Substituents (3 slides) 4.3. Extension - Extra Functional Groups (2 slides) 4.4. Chain Extension / Contraction (2 slides) 4.5. Ring Expansion / Contraction (2 slides) 4.6. Ring Variations (4 slides) 4.7. Isosteres and Bio-isosteres (3 slides) [39 slides]

DRUG DESIGN AND DEVELOPMENT Stages 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

4. DRUG DESIGN - OPTIMISING BINDING INTERACTIONS AIM - To optimise binding interactions with target REASONS To increase activity and reduce dose levels To increase selectivity and reduce side effects STRATEGIES Vary alkyl substituents Vary aryl substituents Extension Chain extensions / contractions Ring expansions / contractions Ring variation Isosteres Simplification Rigidification

4.1 Vary Alkyl Substituents Rationale : Alkyl group in lead compound may interact with hydrophobic region in binding site Vary length and bulk of group to optimise interaction

4.1 Vary Alkyl Substituents Rationale : Vary length and bulk of alkyl group to introduce selectivity Binding region for N Receptor 1 Receptor 2

4.1 Vary Alkyl Substituents Rationale: Vary length and bulk of alkyl group to introduce selectivity Example: Selectivity of adrenergic agonists and antagonists for b-adrenoceptors over a-adrenoceptors

4.1 Vary Alkyl Substituents Adrenaline Salbutamol (Ventolin) (Anti-asthmatic) Propranolol (b-Blocker)

a-Adrenoceptor H-Bonding region Ionic bonding Van der Waals

a-Adrenoceptor ADRENALINE

a-Adrenoceptor

b-Adrenoceptor ADRENALINE

b-Adrenoceptor SALBUTAMOL

b-Adrenoceptor

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor SALBUTAMOL

a-Adrenoceptor

4.1 Vary Alkyl Substituents Notes on synthetic feasibility of analogues Feasible to remove alkyl substituents on heteroatoms and replace with other alkyl substituents Difficult to modify alkyl substituents on the carbon skeleton of a lead compound. Full synthesis is usually required

4.1 Vary Alkyl Substituents Methods

4.2 Vary Aryl Substituents Vary substituents Vary substitution pattern Weak H-Bond Binding Region (H-Bond) (for Y) Strong H-Bond (increased activity)

4.2 Vary Aryl Substituents Vary substitution pattern to enhance binding interactions Benzopyrans Anti-arrhythmic activity best when substituent is at 7-position

4.2 Vary Aryl Substituents Vary substitution pattern to enhance binding strength indirectly - electronic effects Binding strength of NH2 as HBD affected by relative position of NO2 Stronger when NO2 is at para position

4.3 Extension - Extra Functional Groups Rationale : To explore target binding site for further binding regions to achieve additional binding interactions RECEPTOR RECEPTOR Extra functional group Unused binding region DRUG DRUG Drug Extension Binding regions Binding group

4.3 Extension - Extra Functional Groups Example : ACE Inhibitors Hydrophobic pocket Vacant EXTENSION Hydrophobic pocket Binding site Binding site

4.4 Chain Extension / Contraction Rationale : Useful if a chain is present connecting two binding groups Vary length of chain to optimise interactions Weak interaction Strong interaction A B Chain extension A B RECEPTOR RECEPTOR Binding regions Binding groups A & B

4.4 Chain Extension / Contraction Example : N-Phenethylmorphine Binding group Optimum chain length = 2

4.5 Ring Expansion / Contraction Rationale : To improve overlap of binding groups with their binding regions R Ring expansion R Hydrophobic regions

4.5 Ring Expansion / Contraction Vary n to vary ring size Example Binding regions Binding site Binding site

4.6 Ring Variations Rationale : Replace aromatic/heterocyclic rings with other ring systems Often done for patent reasons General structure for NSAIDS Core scaffold

4.6 Ring Variations Rationale : Example : Sometimes results in improved properties Example : Ring variation Antifungal agent Improved selectivity vs. fungal enzyme

4.6 Ring Variations Example - Nevirapine (antiviral agent) Additional binding group

4.6 Ring Variations Example - Pronethalol (b-blocker) Selective for b-receptors over a-receptors

4.7 Isosteres and Bio-isosteres Rationale (isosteres) : Replace a functional group with a group of same valency (isostere) e.g. OH replaced by SH, NH2, CH3 O replaced by S, NH, CH2 Leads to more controlled changes in steric/electronic properties May affect binding and / or stability

4.7 Isosteres and Bio-isosteres Useful for SAR Propranolol (b-blocker) Replacing OCH2 with CH=CH, SCH2, CH2CH2 eliminates activity Replacing OCH2 with NHCH2 retains activity Implies O involved in binding (HBA)

4.7 Isosteres and Bio-isosteres Rationale (Bio-isosteres) : Replace a functional group with another group which retains the same biological activity Not necessarily the same valency Example antipsychotics Pyrrole ring = bio-isostere for amide group Improved selectivity for D3 receptor over D2 receptor