The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor

被引：13

作者：

Naidu, B. Narasimhulu ^{[1
]}

Walker, Michael A. ^{[1
]}

Sorenson, Margaret E. ^{[1
]}

Ueda, Yasutsugu ^{[1
]}

Matiskella, John D. ^{[1
]}

Connolly, Timothy P. ^{[1
]}

Dicker, Ira B. ^{[2
]}

Lin, Zeyu ^{[2
]}

Bollini, Sagarika ^{[2
]}

Terry, Brian J. ^{[2
]}

Higley, Helen ^{[2
]}

Zheng, Ming ^{[3
]}

Parker, Dawn D. ^{[3
]}

Wu, Dedong ^{[4
]}

Adams, Stephen ^{[3
]}

Krystal, Mark R. ^{[2
]}

Meanwell, Nicholas A. ^{[1
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Dept Discovery Chem, 5 Res Pkwy, Wallingford, CT 06492 USA

[2] Bristol Myers Squibb Res & Dev, Virol, 5 Res Pkwy, Wallingford, CT 06492 USA

[3] Bristol Myers Squibb Res & Dev, 5 Res Pkwy, Wallingford, CT 06492 USA

[4] Bristol Myers Squibb Res & Dev, Mat Chem & Crystallog, 5 Res Pkwy, Wallingford, CT 06492 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 12期

关键词：

HIV-1; integrase; Strand transfer inhibitors; INSTI; Pyrimidinone carboxamides; Antiviral activity; Pharmacokinetics; RALTEGRAVIR; CHEMOTYPE;

D O I：

10.1016/j.bmcl.2018.05.027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.

引用

页码：2124 / 2130

页数：7

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