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
Phomactin A (1) is a selective antagonist of platelet activating factor (PAF). Herein, we report our progress toward the construction of the oxadecalin core of 1. This route is based on the Diels-Alder cycloaddition of an appropriately functionalized vinyl pyran and a complementary dienophile. A model of this reaction involving 2 and maleic anhydride was conducted. Adduct 3 contains the correct stereochemical arrangements between functional groups necessary for gaining access to phomactin A. Reaction: see text.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Naphthalenes/chemical synthesis , Fungi/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Maleic Anhydrides/chemistry , Models, Chemical , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , StereoisomerismABSTRACT
Glycoproteins contain carbohydrate and peptide sectors. As a model for studying whether there exists stereochemical "communication" between the two domains, we prepared two glycopeptides differing only in the absolute stereochemistry of the peptide domain (L-peptide vs D-peptide). High-field NMR spectroscopy revealed that there are distinct and measurable differences, indicating that the two domains are at some level interactive.
