Dihydroxypyrimidine-4-carboxamides as Novel Potent and Selective HIV Integrase Inhibitors

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• 作者：Paola Pace ; M. Emilia Di Francesco ; Cristina Gardelli ; Steven Harper ; Ester Muraglia ; Emanuela Nizi ; Federica Orvieto ; Alessia Petrocchi ; Marco Poma ; Michael Rowley ; Rita Scarpelli ; Ralph Laufer ; Odal
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 3, 2007
• 年：2007
• 卷：50
• 期：9
• 页码：2225 - 2239
• 全文大小：223K
• 年卷期：v.50,no.9(May 3, 2007)
• ISSN：1520-4804

文摘

Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes requiredfor replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has alsorecently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these moleculeswere made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interestingcompounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide 38, with a CIC₉₅ of 78 nM in the cell-based assay in the presence of serum proteins.The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys)and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically usefulantiviral agent.