RESUMO
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a â¼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.
Assuntos
Inibidores Enzimáticos/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pirazolonas/farmacologia , Quinolinas/farmacologia , Esquizofrenia/tratamento farmacológico , Administração Oral , Animais , Cristalografia por Raios X , Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazolonas/administração & dosagem , Pirazolonas/química , Quinolinas/administração & dosagem , Quinolinas/química , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Azetidinas/química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo T/química , Piperidinas/química , Compostos de Espiro/química , Animais , Azetidinas/síntese química , Azetidinas/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Desenho de Fármacos , Humanos , Dor/tratamento farmacológico , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
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
Assuntos
Aminopiridinas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Espectroscopia de Ressonância Magnética , Bibliotecas de Moléculas Pequenas/química , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
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.