title: Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors.
abstract: Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
authors.affiliation: Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti S.p.A. (Merck Research Laboratories, Rome), Via Pontina Km 30,600, 00040 Pomezia, Italy. paola_pace@merck.com
authors.forename: Paola
authors.initials: P
authors.lastname: Pace
authors.forename: M Emilia
authors.initials: ME
authors.lastname: Di Francesco
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.forename: Federica
authors.initials: F
authors.lastname: Orvieto
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.forename: Marco
authors.initials: M
authors.lastname: Poma
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Odalys
authors.initials: O
authors.lastname: Gonzalez Paz
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Fabio
authors.initials: F
authors.lastname: Bonelli
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Kara A
authors.initials: KA
authors.lastname: Stillmock
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
mesh_terms: D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004285:Dogs; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D008253:Macaca mulatta; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication
chemical_list: C520648:2-(1-(dimethylamino)-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide; D001798:Blood Proteins; D019428:HIV Integrase Inhibitors; D011725:Pyridines; D011743:Pyrimidines