ABSTRACT
A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.
Subject(s)
Azetidines/chemistry , Calcium Channel Blockers/chemical synthesis , Calcium Channels, T-Type/chemistry , Piperidines/chemistry , Spiro Compounds/chemistry , Animals , Azetidines/chemical synthesis , Azetidines/therapeutic use , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/therapeutic use , Calcium Channels, T-Type/metabolism , Drug Design , Humans , Pain/drug therapy , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper
Subject(s)
Aminopyridines/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Small Molecule Libraries/chemistry , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
