title: 4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, IRBM-MRL Rome, Via Pontina, Km 30.600, 00040 Pomezia, Rome, Italy. Vincenzo_summa@merck.com
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.forename: Victor G
authors.initials: VG
authors.lastname: Matassa
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Odalys Gonzalez
authors.initials: OG
authors.lastname: Paz
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Paola
authors.initials: P
authors.lastname: Pace
mesh_terms: 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
chemical_list: D000577:Amides; D019428:HIV Integrase Inhibitors; D011743:Pyrimidines; D011744:Pyrimidinones