RESUMO
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Three-dimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues. We previously developed a simple method to generate 3D tissue in a short period by coating the cell surfaces with extracellular matrix proteins. We hypothesized that this 3D cardiac tissue could be used for simultaneous evaluation of drug-induced repolarization and contractility. In the present work, we examined the effects of several compounds with different mechanisms of action by cell motion imaging. Consequently, human ether-a-go-go-related gene (HERG) channel blockers with high arrhythmogenic risk caused prolongation of contraction-relaxation duration and arrhythmia-like waveforms. Positive inotropic drugs, which increase intracellular Ca2+ levels or myocardial Ca2+ sensitivity, caused an increase in maximum contraction speed (MCS) or average deformation distance (ADD) (ouabain, 138% for MCS at 300 nM; pimobendane, 132% for ADD at 3 µM). For negative inotropic drugs, verapamil reduced both MCS and ADD (61% at 100 nM). Thus, this 3D cardiac tissue detected the expected effects of various cardiovascular drugs, suggesting its usefulness for cardiotoxicity evaluation.
RESUMO
A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.
Assuntos
Fármacos Antiobesidade/química , Imidazolinas/química , Piridonas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Cães , Descoberta de Drogas , Humanos , Imidazolinas/síntese química , Imidazolinas/farmacocinética , Camundongos , Piridonas/síntese química , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.
Assuntos
Encéfalo/metabolismo , Antagonistas de Entorpecentes , Nitrilas/química , Pirazóis/química , Administração Oral , Animais , Humanos , Camundongos , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Ratos , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacocinética , Cicloexanos/química , Cicloexanos/farmacocinética , Antagonistas de Entorpecentes , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Benzimidazóis/síntese química , Encéfalo/metabolismo , Linhagem Celular , Cicloexanos/síntese química , Cães , Haplorrinos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Ratos , Receptores Opioides/metabolismo , Receptor de NociceptinaRESUMO
A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.
Assuntos
Cicloparafinas/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Antagonistas de Entorpecentes , Piridinas/administração & dosagem , Piridinas/química , Administração Oral , Animais , Fenômenos Químicos , Físico-Química , Cães , Canais de Potássio Éter-A-Go-Go/metabolismo , Hepatócitos/metabolismo , Humanos , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/classificação , Ratos , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
To clarify the functional role of endothelin-A/endothelin- B (ETA/ETB) receptors in congestive heart failure (CHF), we examined the effects of a non-selective endothelin receptor agonist, endothelin-1 (ET-1), and a selective ETB receptor agonist, sarafotoxin S6c. CHF was induced in dogs by rapid ventricular pacing and resulted in decreased left ventricular dp/dtmax, decreased cardiac output and increased pulmonary vascular resistance. Sarafotoxin S6c (0.3 nmol/kg) resulted in decreased left ventricular dp/dtmax (-26 +/- 2%), decreased cardiac output (-47 +/- 3%) and increased pulmonary vascular resistance (+48 +/- 10%) in dogs without CHF. The effects of sarafotoxin S6c were attenuated in dogs with CHF (-12 +/- 5% in left ventricular dp/dtmax, -19 +/- 5% in cardiac output and +7 +/- 5% in pulmonary vascular resistance). In contrast, ET-1 (0.5 nmol/kg) had no effect on left ventricular dp/dtmax in dogs without CHF and increased left ventricular dp/dtmax by 16 +/- 3% in dogs with CHF. These data indicate that reduced cardiac contractile and pulmonary vasoconstrictor responses via the ETB receptor are attenuated and that responses mediated by the ETA receptor are more prominent in the context of CHF. This suggests a functional shift of endothelin receptor subtypes in CHF.