RESUMO
We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/efeitos dos fármacos , Descoberta de Drogas , Epilepsia Generalizada/tratamento farmacológico , Animais , Canais de Cálcio Tipo T/fisiologia , Modelos Animais de Doenças , Humanos , Camundongos , RatosRESUMO
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Assuntos
Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Cetonas/farmacologia , Humanos , Modelos Moleculares , Monócitos/efeitos dos fármacosRESUMO
A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.
Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Epilepsia/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Animais , Anticonvulsivantes/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Bloqueadores dos Canais de Cálcio/farmacocinética , Canais de Cálcio Tipo T/metabolismo , Modelos Animais de Doenças , Cães , Eletroencefalografia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Humanos , Excitação Neurológica/efeitos dos fármacos , Masculino , Pirazóis/farmacocinética , Ratos WistarRESUMO
[reaction: see text] Chiral 1-aryl-6-(hydroxymethyl)-2-ketopiperazines can be prepared via an operationally simple, 6-exo epoxide ring-opening cyclization to form the ketopiperazine C6-N1 bond in high yields and with excellent enantiomeric purity.
RESUMO
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Renina/antagonistas & inibidores , Cristalografia por Raios X , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).