在恒河猴体内具有活性的三唑类CYP11B2抑制剂的发现。
Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.
作者信息
Hoyt Scott B, Petrilli Whitney, London Clare, Liang Gui-Bai, Tata Jim, Hu Qingzhong, Yin Lina, van Koppen Chris J, Hartmann Rolf W, Struthers Mary, Wisniewski Tom, Ren Ning, Bopp Charlene, Sok Andrea, Cai Tian-Quan, Stribling Sloan, Pai Lee-Yuh, Ma Xiuying, Metzger Joe, Verras Andreas, McMasters Daniel, Chen Qing, Tung Elaine, Tang Wei, Salituro Gino, Buist Nicole, Clemas Joe, Zhou Gaochao, Gibson Jack, Maxwell Carrie Ann, Lassman Mike, McLaughlin Theresa, Castro-Perez Jose, Szeto Daphne, Forrest Gail, Hajdu Richard, Rosenbach Mark, Xiong Yusheng
机构信息
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Department of Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrücken, Germany.
出版信息
ACS Med Chem Lett. 2015 Jul 17;6(8):861-5. doi: 10.1021/acsmedchemlett.5b00048. eCollection 2015 Aug 13.
Abstract
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
摘要
从活性化合物到先导化合物的研究工作导致发现了化合物19，它是一种有效的CYP11B2抑制剂，对相关细胞色素P450（CYP）具有高选择性，在大鼠和恒河猴中具有良好的药代动力学性质，以及类似先导化合物的物理性质。在恒河猴药效学模型中，化合物19显示出强大的、剂量依赖性的醛固酮降低功效，对皮质醇水平无明显影响。
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