RESUMO
We have designed a series of potent EP1 receptor antagonists. These antagonists are a series of 2-(1H-indazol-1-yl)-thiazoles in which the core structure was replaced with pyrazole-phenyl groups. In preliminary conscious rat cystometry experiments, two representative candidates, 2 and 22, increased bladder capacity. In particular, the increase using 22 was approximately 2-fold that of the baseline. More detailed profiling of this compound and further optimization of this series promises to provide a novel class of drug for treating overactive bladder (OAB).
Assuntos
Indazóis/química , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Tiazóis/química , Animais , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ligação Proteica , Ratos , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária Hiperativa/tratamento farmacológicoRESUMO
We describe a medicinal chemistry approach for generating a series of 2-(1H-pyrazol-1-yl)thiazoles as EP1 receptor antagonists. To improve the physicochemical properties of compound 1, we investigated its structure-activity relationships (SAR). Optimization of this lead compound provided small compound 25 which exhibited the best EP1 receptor antagonist activity and a good SAR profile.
Assuntos
Pirazóis/química , Pirazóis/farmacologia , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/metabolismo , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/metabolismoRESUMO
We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics.
Assuntos
Pirazóis/farmacologia , Receptores de Prostaglandina E Subtipo EP1/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Humanos , Camundongos , Modelos Moleculares , Pirazóis/farmacocinética , Receptores de Prostaglandina E Subtipo EP1/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
We previously discovered that indazole derivative 8 was a highly selective ß3-adrenergic receptor (ß3-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent ß3-AR agonist (EC50 = 18 nM) being inactive to ß1-, ß2-, and α1A-AR (ß1/ß3, ß2/ß3, and α1A/ß3 > 556-fold). Compound 15 showed dose-dependent ß3-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available ß3-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Indazóis/farmacologia , Administração Oral , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 3/química , Animais , Cães , Descoberta de Drogas , Humanos , Indazóis/efeitos adversos , Indazóis/química , RatosRESUMO
Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human ß3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant ß3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the α1A-AR (EC50 = 219 nM, selectivity: α1A/ß3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for ß3-AR agonistic activity versus α1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent ß3-AR agonistic activity (EC50 = 13 nM) and high selectivity (α1A/ß3 = >769-fold). Compound 11 was also inactive toward ß1 and ß2-ARs and showed dose dependent ß3-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.