ABSTRACT
Guided by structure-based design, we synthesized two novel series of potent inhibitors of BACE1 and generated extensive SAR around both the prime and non-prime side binding pockets. The key feature of both series is a cyclic amine motif specifically crafted to achieve interactions with both the flap and with the S2' pocket.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Design , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Animals , Crystallography, X-Ray , Disease Models, Animal , Humans , Imidazolidines/chemistry , Mice , Mice, Transgenic , Models, Molecular , Molecular Conformation , Molecular Structure , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
Based on a lead compound identified from the patent literature, we developed patentably novel BACE-1 inhibitors by introducing a cyclic amine scaffold as embodied by 1a and 1b. Extensive SAR studies assessed a variety of isophthalamide replacements including substituted pyrrolidinones and ultimately led to the identification of 11. Due to its favorable overall profile, 11 has been extensively profiled in various in vivo settings.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Administration, Oral , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Humans , Hydrogen Bonding , Mice , Mice, Transgenic , Models, Molecular , Phenols/chemistry , Protease Inhibitors/pharmacology , Pyrrolidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/metabolism , Cell Line , Crystallography, X-Ray , Humans , Hydrogen Bonding , Models, Molecular , Piperidines/chemical synthesis , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrrolidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of pyrroloquinazolines has been discovered that represent novel small molecule inhibitors of the intramolecular ligand of the thrombin receptor. Analogs were prepared to study the structure-activity relationships of substitution at the N 1, N3, and N7 positions of the heterocycle. Compounds 4e and 4f have been identified with IC50's of 56 and 52 nM, respectively.
