RESUMEN
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
Asunto(s)
Arginina/análogos & derivados , Flavonas/química , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Arginina/síntesis química , Arginina/química , Arginina/farmacología , Encéfalo/metabolismo , Células CACO-2 , Permeabilidad de la Membrana Celular , Conducta Alimentaria/efectos de los fármacos , Flavonas/síntesis química , Flavonas/farmacología , Células HEK293 , Humanos , Masculino , Membranas Artificiales , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Mutación , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/genética , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/farmacocinética , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Relación Estructura-ActividadRESUMEN
Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.
Asunto(s)
Benzofuranos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Benzofuranos/síntesis química , Benzofuranos/química , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The total synthesis of (+/-)-goniomitine has been accomplished in 17 linear steps with 5.2% overall yield starting from commercially available delta-valerolactam. A synthetic highlight includes the first application of a formal [3 + 2] cycloaddition between a highly functionalized nitrile and a donor-acceptor cyclopropane to prepare an indole nucleus. The use of a microwave reactor is shown to greatly improve the reaction times for two steps.