Arban Roberto, Benedetti Roberto, Bonanomi Giorgio, Capelli Anna-Maria, Castiglioni Emiliano, Contini Stefania, Degiorgis Fabio, Di Felice Pina, Donati Daniele, Fazzolari Elettra, Gentile Gabriella, Marchionni Chiara, Marchioro Carla, Messina Flavia, Micheli Fabrizio, Oliosi Beatrice, Pavone Francesca, Pasquarello Alessandra, Perini Benedetta, Rinaldi Marilisa, Sabbatini Fabio M, Vitulli Giovanni, Zarantonello Paola, Di Fabio Romano, St-Denis Yves
GlaxoSmithKline Medicines Center, Psychiatry CEDD, Via A. Fleming 4, 37135 Verona, Italy.
ChemMedChem. 2007 Apr;2(4):528-40. doi: 10.1002/cmdc.200600257.
Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.
本文介绍了两类新型强效且具选择性的促肾上腺皮质激素释放因子（CRF）(1)受体拮抗剂。通过对顶部胺基和底部苯基取代基进行修饰来探索通用模板3和4，从而优化了体外亲和力和药代动力学特征。CRF(1)拮抗剂顶部区域中典型的烷基链被取代的杂芳基部分所取代，使得代谢稳定性得到显著提高。当这些化合物进行体内给药时，这种改善很明显：几种化合物表现出低血浆清除率、良好的口服生物利用度和高脑渗透率。由于其出色的药代动力学特征，这些CRF(1)拮抗剂，以化合物4 fi（4-(4-溴-3-甲基-1H-吡唑-1-基)-7-(2,4-二氯苯基)-2-甲基-6,7-二氢-5H-吡咯并[2,3-d]嘧啶）为例，口服给药时产生剂量依赖性的“抗焦虑样”效应，减少了幼鼠的发声。
