RESUMO
A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Aldeídos/química , Aminas/química , Benzimidazóis/química , Catálise , Simulação por Computador , Histamina/metabolismo , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Receptores Acoplados a Proteínas G/química , Receptores Histamínicos/química , Receptores Histamínicos H4 , Relação Estrutura-AtividadeRESUMO
A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication.
Assuntos
Compostos Bicíclicos com Pontes/química , Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Piperidinas/química , Animais , Sítios de Ligação , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Camundongos , Piperidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
Assuntos
Catepsinas/antagonistas & inibidores , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Linhagem Celular , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Modelos Químicos , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Antagonists of the alpha(1)-adrenergic receptors (alpha(1)-ARs) are useful for the treatment of benign prostatic hyperplasia. A series of potent and subtype-selective alpha(1a)-AR antagonists has been synthesized, displaying in vitro binding affinity in the low the nanomolar range.
Assuntos
Antagonistas Adrenérgicos/síntese química , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Isoxazóis , Piperazinas/síntese química , Piperazinas/farmacologia , Ligação Proteica , Receptores Adrenérgicos alfa 1 , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
The syntheses and biological activities of a novel series of 2,4- and 2,5-disubstituted thiophenes are reported. These analogues have shown excellent affinity and selectivity against alpha(1)-adrenoreceptor subtypes.