胃饥饿素受体反向激动剂的结构优化以提高亲脂性并避免基于机制的CYP3A4失活
Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation.
作者信息
Takahashi Bitoku, Funami Hideaki, Shibata Makoto, Maruoka Hiroshi, Koyama Makoto, Kanki Satomi, Muto Tsuyoshi
机构信息
Asubio Pharma Co., Ltd.
出版信息
Chem Pharm Bull (Tokyo). 2015;63(10):825-32. doi: 10.1248/cpb.c15-00285.
Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.
报道了2-氨基烟酰胺衍生物作为胃饥饿素受体反向激动剂的结构优化。为避免细胞色素P450 3A4（CYP3A4）的基于机制的失活（MBI），对先导化合物的1,3-苯并二氧杂环进行了修饰。同时实现了主要活性和亲脂性的提高，得到了化合物18a，其显示出高亲脂性配体效率（LLE）和低MBI活性。
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