title: Case histories in drug discovery and design.
abstract: Seven highly informative accounts of drug discovery and design were delivered by members of an international panel of speakers. The evolution of a new drug treatment for schizophrenia commenced with the observation that chlorpromazine possessed "neuroleptic" activity and progressed through studies with various dopamine and serotonin antagonists to ultimately lead to the discovery of risperidone. The 20-amino-acid peptide bivalirudin was rationally derived from hirudin. The alkoxypolyaryl derivative LY-303366 emerged from a second-generation chemical program with the aim of improving the solubility and pharmacokinetic profile of cilofungin. Antiviral activity in the low nanomolar range, combined with oral bioavailability and a clean safety profile, resulted in the development of saquinavir mesylate as the first HIV proteinase inhibitor to become available as a marketed drug. The marimastat drug design program was based on knowledge of the collagenase cleavage site, and molecules incorporated features to allow them to coordinate with the active site zinc atom and side chains that allowed interaction with the enzyme subsites. Initial lead compounds in the anastrozole development program were azoles incorporated onto nonsteroidal estrogen-like scaffolds. Chance synthesis of a nitrile intermediate needed for the naphthalene analogues and further elaboration eventually led to this potent and selective aromatase inhibitor. Rosiglitazone emerged from an SAR program on ciglitazone in which the lipophilic cyclohexyl group was replaced by aromatic and polar groups.