Velaparthi Upender, Wittman Mark, Liu Peiying, Carboni Joan M, Lee Francis Y, Attar Ricardo, Balimane Praveen, Clarke Wendy, Sinz Michael W, Hurlburt Warren, Patel Karishma, Discenza Lorell, Kim Sean, Gottardis Marco, Greer Ann, Li Aixin, Saulnier Mark, Yang Zheng, Zimmermann Kurt, Trainor George, Vyas Dolatrai
Discovery Chemistry, Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Co., Wallingford, Connecticut 06492, USA.
J Med Chem. 2008 Oct 9;51(19):5897-900. doi: 10.1021/jm800832q. Epub 2008 Sep 3.
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
我们之前报道过，1（BMS-536924），一种胰岛素样生长因子-1受体的苯并咪唑抑制剂，已在体内显示出抗肿瘤活性。该先导化合物被发现具有强效的CYP3A4抑制作用、由PXR反式激活介导的CYP3A4诱导作用、较差的水溶性以及较高的血浆蛋白结合率。在此，我们披露该化学类型的演变以解决这些问题。这一努力产生了10（BMS-695735），其表现出改善的药代动力学性质、较低的药物相互作用风险以及在多个异种移植模型中的体内疗效。
