RESUMO
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Assuntos
Amidinas/química , Química Farmacêutica/métodos , Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Animais , Desenho de Fármacos , Eletrofisiologia , Indóis/química , Concentração Inibidora 50 , Canais Iônicos/química , Masculino , Modelos Químicos , Naproxeno/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Isoxazóis/farmacologia , Receptores de Esteroides/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Isoxazóis/farmacocinética , Macaca mulatta , Receptor de Pregnano X , Ratos , Ratos Sprague-DawleyRESUMO
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.
Assuntos
Acetamidas/síntese química , Amidas/síntese química , Compostos de Aminobifenil/síntese química , Benzoatos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Encéfalo/metabolismo , Ciclopropanos/síntese química , Medula Espinal/metabolismo , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Compostos de Aminobifenil/farmacocinética , Compostos de Aminobifenil/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/farmacocinética , Benzoatos/farmacologia , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células CHO , Chlorocebus aethiops , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Coelhos , Ensaio Radioligante , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
A novel class of 2,3-diaminopyridine bradykinin B1 receptor antagonists is disclosed. Structure-activity relationship studies (SARs) that led to compounds with significantly improved potency and pharmacokinetic properties relative to the lead compound are described.
Assuntos
Aminopiridinas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Piridinas/síntese química , Aminopiridinas/química , Desenho de Fármacos , Humanos , Cinética , Modelos Moleculares , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Bradykinin B1 receptor antagonists embody a potentially novel approach for the treatment of chronic pain and inflammation. A series of 2,3-diaminopyridine B1 antagonists was optimized to have sub-nanomolar affinity and good pharmacokinetic properties. Lead compounds were shown to exhibit good efficacy in rabbit in vivo models of pain and inflammation.
Assuntos
Aminopiridinas/síntese química , Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Antagonistas de Receptor B1 da Bradicinina , Aminopiridinas/química , Aminopiridinas/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Cães , Meia-Vida , Inflamação/tratamento farmacológico , Medição da Dor , Coelhos , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (1), along with the results of its in vitro and in vivo evaluation as a pro-drug targeted at prostate cancer cells. Prostate-derived tumors are known to produce significant amounts of prostate specific antigen (PSA), a serine protease with chymotrypsin-like properties. Earlier work in these laboratories established that an appropriately engineered peptidyl pro-drug will release active cytotoxic agent strictly within the microenvironment of the tumor tissue (Garsky, V. M., et al. J. Med.Chem. 2001, 44, 4216-4224). Conjugate 5, which features an octapeptide segment attached by an ester linkage at the 4-position of vinblastine (1), undergoes rapid cleavage by PSA (T(1/2) = 12 min) between the Gln and Ser residues. In nude mouse xenograft studies, 5 reduced circulating PSA levels by 99% and tumor weight by 85% at a dose just below its MTD. By contrast, the putative end-point metabolite, the cytotoxic agent des-acetyl vinblastine (1b), was ineffective in reducing PSA levels and tumor burden at its maximum tolerated doses. Additional data from metabolism studies on 5 support the supervention of a novel in vivo processing mechanism, the spontaneous release of 1b from a dipeptidyl intermediate driven by favorable diketopiperazine formation.
