518047-45-5Relevant academic research and scientific papers
Discovery and synthesis of HIV integrase inhibitors: Development of potent and orally bioavailable N-methyl pyrimidones
Gardelli, Cristina,Nizi, Emanuela,Muraglia, Ester,Crescenzi, Benedetta,Ferrara, Marco,Orvieto, Federica,Pace, Paola,Pescatore, Giovanna,Poma, Marco,Ferreira, Maria Del Rosario Rico,Scarpelli, Rita,Homnick, Carl F.,Ikemoto, Norihiro,Alfieri, Anna,Verdirame, Maria,Bonelli, Fabio,Paz, Odalys Gonzalez,Taliani, Marina,Monteagudo, Edith,Pesci, Silvia,Laufer, Ralph,Felock, Peter,Stillmock, Kara A.,Hazuda, Daria,Rowley, Michael,Summa, Vincenzo
, p. 4953 - 4975 (2008/03/14)
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 viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against 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 that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
4,5-Dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species
Summa, Vincenzo,Petrocchi, Alessia,Matassa, Victor G.,Gardelli, Cristina,Muraglia, Ester,Rowley, Michael,Paz, Odalys Gonzalez,Laufer, Ralph,Monteagudo, Edith,Pace, Paola
, p. 6646 - 6649 (2007/10/03)
The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.
