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

• DOI: 10.1021/jm0704705
• Publication Date: 2007-09-08T11:00:27Z
• Authors: Cristina Gardelli; Emanuela Nizi; Ester Muraglia; Benedetta Crescenzi; Marco Ferrara; Federica Orvieto; Paola Pace; Giovanna Pescatore; Marco Poma; Maria del Rosario...; Rita Scarpelli; Carl F. Homnick; Norihiro Ikemoto; Anna Alfieri; Maria Verdirame; Fabio Bonelli; Odalys Gonzalez Paz; Marina Taliani; Edith Monteagudo; Silvia Pesci; Ralph Laufer; Peter Felock; Kara A. Stillmock; Daria Hazuda; Michael Rowley; Vincenzo Summa
• Keywords: Integrase inhibitor; Structure–activity relationship

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