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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN:

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 7: Section 10.4. Contents Part 7: Section 10.4 4.12. Case Study - Development of Oxamniquine [9 slides]. Oxamniquine. 4.12 CASE STUDY - Development of Oxamniquine.

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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN:

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  1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 7: Section 10.4

  2. Contents Part 7: Section 10.4 4.12. Case Study - Development of Oxamniquine [9 slides]

  3. Oxamniquine 4.12 CASE STUDY - Development of Oxamniquine • Used vs schistosomiasis (bilharzia) - a water borne disease • carried by snails • 200 million sufferers in third world

  4. Lucanthone Mirasan - Stage 1 - Find a Lead Compound • Active • But low activity, low range, orally • inactive and slightly toxic Stage 2 - Simplification Stage 3 - Vary aromatic substituents • Active in mice • Inactive in man • Electronegative Cl beneficial • at position shown

  5. Stage 4 - SAR studies • Side chain and aromatic ring are important binding groups • Both nitrogens are important • Nitrogens are on a flexible chain - conformational flexibility Stage 5 - Rigidification One bond ‘locked’ Activity increases Inactive in man, active in monkeys Rigidification has retained active conformation Two bonds ‘locked’ Activity increases in mice Rigidification has retained active conformation Novel structure and so worth testing previous strategies again

  6. Stage 6 - Vary substituents and substituent positions on aromatic ring • Substitution pattern on aromatic ring is essential • Electron withdrawing groups are best for activity - replacing Cl with NO2 increases activity • Nitro group reduces basicity of the aromatic nitrogen • pKa is increased and structure is less easily ionised • Passes through cell membranes more easily

  7. STERIC BLOCK No interaction RECEPTOR RECEPTOR Stage 7 - Vary side chain substituents • Secondary amine better than primary or tertiary at end of chain • Optimum length of alkyl group on N = 4C • Acyl groups eliminate activity (implies N is protonated for ionic interaction)

  8. + + - - • Branching on side chain eliminates activity • Prevents molecule adopting active conformation Stage 7 - Vary side chain substituents Branched alkyl groups increase activity. Implies stronger vdw interactions to bulky pocket or benefit in increased lipophilicity

  9. Asymmetric centre Stage 8 - Other strategies gave no improvement (e.g. chain extension eliminates activity Optimum Structure

  10. Stage 9 - Drug Metabolism Studies • Oxidation of aromatic methyl group to give oxamniquine • Oxaminiquine is the active drug • Methyl analogue is acting as a prodrug

  11. - RECEPTOR IONIC BINDING REGIONS VAN DER WAALS H-BONDING Stage 10 - Proposed binding interactions

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