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[4-[[1-(3-氟苯基)甲基]-1H-吲唑-5-基氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]氨基甲酸(3S)-3-吗啉基甲酯(BMS-599626)的发现及临床前评估，一种人表皮生长因子受体1和2激酶的选择性口服有效抑制剂

Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases.

作者信息

Gavai Ashvinikumar V, Fink Brian E, Fairfax David J, Martin Gregory S, Rossiter Lana M, Holst Christian L, Kim Soong-Hoon, Leavitt Kenneth J, Mastalerz Harold, Han Wen-Ching, Norris Derek, Goyal Bindu, Swaminathan Shankar, Patel Bharat, Mathur Arvind, Vyas Dolatrai M, Tokarski John S, Yu Chiang, Oppenheimer Simone, Zhang Hongjian, Marathe Punit, Fargnoli Joseph, Lee Francis Y, Wong Tai W, Vite Gregory D

机构信息

Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, USA.

出版信息

J Med Chem. 2009 Nov 12;52(21):6527-30. doi: 10.1021/jm9010065.

DOI:10.1021/jm9010065
PMID:19821562
Abstract

Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.

摘要

一系列4-[1H-吲唑-5-基氨基]吡咯并[2,1-f][1,2,4]三嗪-6-氨基甲酸酯的构效关系确定了具有优异生化活性和激酶选择性的双重人表皮生长因子受体（HER）1/HER2激酶抑制剂。基于其良好的药代动力学特性以及在HER1和HER2驱动的肿瘤模型中的强大体内活性，13（BMS-599626）被选为治疗实体瘤的临床候选药物。

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