Discovery and Synthesis of HIV Integrase Inhibitors: Development of Potent and Orally Bioavailable N-Methyl Pyrimidones

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• 作者：Cristina Gardelli ; Emanuela Nizi ; Ester Muraglia ; Benedetta Crescenzi ; Marco Ferrara ; Federica Orvieto ; Paola Pace ; Giovanna Pescatore ; Marco Poma ; Maria del Rosario Rico Ferreira ; Rita Scarpelli ; Car
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4953 - 4975
• 全文大小：398K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication:a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viralgenome into the human genome and, therefore, represents an attractive target for chemotherapeutic interventionagainst AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents thatexhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compoundsbased on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds inthis series is the 2-N-Me-morpholino derivative 27a, which shows a CIC₉₅ of 65 nM in the cell in thepresence of serum. The compound has favorable pharmacokinetic properties in three preclinical species andshows no liabilities in several counterscreening assays.