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

1 © Contents 4.12.Case Study - Development of Oxamniquine [9 slides]

1 © 4.12 CASE STUDY - Development of Oxamniquine Used vs schistosomiasis (bilharzia) - a water borne diseaseUsed vs schistosomiasis (bilharzia) - a water borne disease carried by snails 200 million sufferers in third world200 million sufferers in third world Oxamniquine

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

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

1 © Stage 6 - Vary substituents and substituent positions on aromatic ring ring Substitution pattern on aromatic ring is essentialSubstitution pattern on aromatic ring is essential Electron withdrawing groups are best for activity - replacing Cl with NO 2 increases activityElectron withdrawing groups are best for activity - replacing Cl with NO 2 increases activity Nitro group reduces basicity of the aromatic nitrogenNitro group reduces basicity of the aromatic nitrogen pK a is increased and structure is less easily ionisedpK a is increased and structure is less easily ionised Passes through cell membranes more easilyPasses through cell membranes more easily

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

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

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

1 © Stage 9 - Drug Metabolism Studies Oxidation of aromatic methyl group to give oxamniquineOxidation of aromatic methyl group to give oxamniquine Oxaminiquine is the active drugOxaminiquine is the active drug Methyl analogue is acting as a prodrugMethyl analogue is acting as a prodrug

1 © RECEPTOR BINDINGREGIONS IONIC VAN DER WAALS H-BONDING - Stage 10 - Proposed binding interactions