ABSTRACT
Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.
ABSTRACT
A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.
Subject(s)
Alkenes/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Alkenes/chemical synthesis , Alkenes/chemistry , Amides/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Imidazoles/chemistry , Protease Inhibitors/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Amyloid Precursor Protein Secretases/metabolism , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Molecular Conformation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Structure, TertiaryABSTRACT
A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.
