RESUMO
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/química , Inibidores de Proteases/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Disponibilidade Biológica , Cães , Etilaminas/síntese química , Etilaminas/farmacocinética , Camundongos , Camundongos Knockout , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/química , Inibidores de Proteases/química , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Etilaminas/síntese química , Etilaminas/farmacologia , Humanos , Camundongos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologiaRESUMO
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Tiazinas/química , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Etilaminas/síntese química , Etilaminas/química , Etilaminas/farmacologia , Humanos , Camundongos , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/farmacocinéticaRESUMO
2-Fluoropyridyl derivatives of allylic alcohols react with xanthates in the presence of lauroyl peroxide to give alkenes, often with high stereoselectivity. If the allylic alcohols are themselves derived from aldehydes or ketones, the overall process becomes a synthetic equivalent of the classical Wittig and related olefination reactions.
RESUMO
BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzotiadiazinas/síntese química , Óxidos S-Cíclicos/síntese química , Etilaminas/síntese química , Administração Oral , Animais , Benzotiadiazinas/farmacocinética , Benzotiadiazinas/farmacologia , Disponibilidade Biológica , Óxidos S-Cíclicos/farmacocinética , Óxidos S-Cíclicos/farmacologia , Cães , Etilaminas/farmacocinética , Etilaminas/farmacologia , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
Assuntos
Doença de Alzheimer/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Etilaminas/síntese química , Etilaminas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Animais , Asparagina/química , Cristalografia por Raios X , Modelos Animais de Doenças , Etilaminas/química , Flúor/química , Camundongos , Estrutura Molecular , Nanotecnologia , Relação Estrutura-AtividadeRESUMO
Adducts from the intermolecular radical addition of N-xanthylacetyl-N-methanesulfanilides to Boc-protected allylamine undergo ring closure with loss of a methanesulfonyl radical to give benzazepin-2-ones. Upon deprotection and exposure to triethylamine, these compounds rearrange into 5-aryl-2-piperidones. This approach also represents a useful route to benzazepin-2-ones unsubstituted on the nitrogen atom of the azepinone ring.