ABSTRACT
A facile method for late stage diversification of lead molecules for the M1 PAM program using biosynthesis is described. Liver microsomes from several species are screened to identify a high turnover system. Subsequent incubations using less than 1â¯mg of substrate generate nanomole quantities of drug metabolites that are purified, characterized by microcryoprobe NMR spectroscopy, and quantified to known concentrations to enable rapid biology testing. The late-stage diversification of lead compounds provides rapid SAR feedback to the medicinal chemistry design cycle.
Subject(s)
Bridged Bicyclo Compounds/metabolism , Cyclohexanes/metabolism , Heterocyclic Compounds/metabolism , Bridged Bicyclo Compounds/chemistry , Cyclohexanes/chemistry , Dose-Response Relationship, Drug , Heterocyclic Compounds/chemistry , Magnetic Resonance Spectroscopy , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Structure-Activity RelationshipABSTRACT
Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.