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
We identified and characterized a series of pyrazole amides as potent, selective Cav3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d, with excellent potencies and/or selectivities toward the Cav3.2- and Cav3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.
Assuntos
Amidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Descoberta de Drogas , Pirróis/farmacologia , Amidas/síntese química , Amidas/química , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Ratos , Relação Estrutura-AtividadeRESUMO
We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.
Assuntos
Amidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Descoberta de Drogas , Pirróis/farmacologia , Amidas/síntese química , Amidas/química , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Ratos , Relação Estrutura-AtividadeRESUMO
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
The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Desenho de Fármacos , Modelos Moleculares , Piperidinas/química , Conformação Proteica , Ratos , Relação Estrutura-Atividade , Difração de Raios XRESUMO
The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Angiotensinogênio/genética , Animais , Animais Geneticamente Modificados , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/química , Humanos , Indicadores e Reagentes , Modelos Moleculares , Piperidinas/química , Ratos , Renina/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.
Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Renina/antagonistas & inibidores , Renina/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Humanos , Modelos Moleculares , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Renina/química , Relação Estrutura-AtividadeRESUMO
New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.
Assuntos
Compostos Bicíclicos com Pontes/classificação , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Renina/antagonistas & inibidores , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
