RESUMO
Chiral N-heterocyclic carbenes (NHCs) promote the asymmetric formal [4 + 2] cycloaddition of alkylarylketenes with ß,γ-unsaturated α-ketocarboxylic esters and amides. Divergent diastereoselectivity is observed in this process, with γ-aryl-ß,γ-unsaturated α-ketocarboxylic esters and amides giving preferentially syn-dihydropyranones (up to 68 : 32 dr syn : anti, up to 98% ee), while γ-alkyl-derivatives generate anti-dihydropyranones (up to 18 : 82 dr syn : anti, up to 75% ee).
Assuntos
Amidas/síntese química , Ácidos Carboxílicos/síntese química , Ésteres/síntese química , Etilenos/síntese química , Compostos Heterocíclicos/química , Cetonas/síntese química , Metano/análogos & derivados , Amidas/química , Ácidos Carboxílicos/química , Cristalografia por Raios X , Ciclização , Ésteres/química , Etilenos/química , Cetonas/química , Metano/química , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
A series of aryloxyazetidines, aryloxypyrrolidines and aryloxypiperidines were designed based on structural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in these new series. Several aryloxyazetidines also showed high levels of selectivity, with one compound, 25, displaying promising in vivo pharmacokinetics and significantly improved aqueous solubility over related compounds containing a biaryl substituent.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Azetidinas/química , Ocitocina/análogos & derivados , Triazóis/química , Administração Oral , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Cães , Humanos , Microssomos Hepáticos/metabolismo , Ocitocina/química , Ocitocina/farmacocinética , Ratos , Receptores de Vasopressinas/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacocinéticaRESUMO
Several potent aryl ether/triazole oxytocin antagonists are described. The lead compound in this series had significantly improved aqueous solubility over related systems containing a biaryl substituent.
Assuntos
Ocitocina/antagonistas & inibidores , Triazóis/síntese química , Triazóis/farmacologia , Administração Oral , Animais , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.