Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors. Issue 13 (1st July 2020)

• Record Type: Journal Article
• Authors: Patel, Manoj; Naidu, B. Narasimhulu; Dicker, Ira; Higley, Helen; Lin, Zeyu; Terry, Brian; Protack, Tricia; Krystal, Mark; Jenkins, Susan; Parker, Dawn; Panja, Chiradeep; Rampulla, Richard; Mathur, Arvind; Meanwell, Nicholas A.; Walker, Michael A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 13(2020)
• Publication Date: 2020-07-01
• Subjects: HIV -- HIV Integrase -- Integrase inhibitor -- Strand transfer inhibitor -- Bridged tricyclic pyrimidinone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115541
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transferase 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. Abstract: 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.