Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors

被引：8

作者：

Patel, Manoj ^{[1
,5
]}

Naidu, B. Narasimhulu ^{[1
,5
]}

Dicker, Ira ^{[2
,5
]}

Higley, Helen ^{[2
]}

Lin, Zeyu ^{[2
]}

Terry, Brian ^{[2
]}

Protack, Tricia ^{[2
]}

Krystal, Mark ^{[2
,5
]}

Jenkins, Susan ^{[1
,5
]}

Parker, Dawn ^{[1
,5
]}

Panja, Chiradeep ^{[3
]}

Rampulla, Richard ^{[4
]}

Mathur, Arvind ^{[4
]}

Meanwell, Nicholas A. ^{[1
]}

Walker, Michael A. ^{[1
,6
]}

机构：

[1] Dept Discovery Chem & Mol Technol, 5 Res Pkwy, Wallingford, CT 06492 USA

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

[3] Biocon Bristol Myers Squibb Res Ctr, Plot 2&3,Bommasandra Ind Estate Phase 4, Bengaluru 560099, Karnataka, India

[4] Bristol Myers Squibb Res & Dev, Dept Discovery Chem Synth, POB 4000, Princeton, NJ 08543 USA

[5] ViiV Healthcare, 36 East Ind Pkwy, Branford, CT 06405 USA

[6] Assembly Biosci Inc, 331 Oyster Point Blvd, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2020年 / 28卷 / 13期

关键词：

RALTEGRAVIR RESISTANCE; DOLUTEGRAVIR; ELVITEGRAVIR; MUTATIONS; EVOLUTION;

D O I：

10.1016/j.bmc.2020.115541

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir. © 2020 Elsevier Ltd

引用

页数：6

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