4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species.
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.
Summa
Vincenzo
V
Department of Medicinal Chemistry, IRBM-MRL Rome, Via Pontina, Km 30.600, 00040 Pomezia, Rome, Italy. Vincenzo_summa@merck.com
Petrocchi
Alessia
A
Matassa
Victor G
VG
Gardelli
Cristina
C
Muraglia
Ester
E
Rowley
Michael
M
Paz
Odalys Gonzalez
OG
Laufer
Ralph
R
Monteagudo
Edith
E
Pace
Paola
P
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D044967:Serum; D013329:Structure-Activity Relationship; D014779:Virus Replication
D000577:Amides; D019428:HIV Integrase Inhibitors; D011743:Pyrimidines; D011744:Pyrimidinones