4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species
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Summa, Vincenzo
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Summa, Vincenzo
Petrocchi, Alessia
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Petrocchi, Alessia
Matassa, Victor G.
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Matassa, Victor G.
Gardelli, Cristina
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Gardelli, Cristina
Muraglia, Ester
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Muraglia, Ester
Rowley, Michael
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Rowley, Michael
Paz, Odalys Gonzalez
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Paz, Odalys Gonzalez
Laufer, Ralph
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Laufer, Ralph
Monteagudo, Edith
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Monteagudo, Edith
Pace, Paola
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机构:IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
Pace, Paola
机构:
[1] IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
[2] IRBM MRL Rome, Dept Drug Metab, I-00040 Monte Porzio Catone, Italy
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.