Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors.
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.
Pace
Paola
P
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
Di Francesco
M Emilia
ME
Gardelli
Cristina
C
Harper
Steven
S
Muraglia
Ester
E
Nizi
Emanuela
E
Orvieto
Federica
F
Petrocchi
Alessia
A
Poma
Marco
M
Rowley
Michael
M
Scarpelli
Rita
R
Laufer
Ralph
R
Gonzalez Paz
Odalys
O
Monteagudo
Edith
E
Bonelli
Fabio
F
Hazuda
Daria
D
Stillmock
Kara A
KA
Summa
Vincenzo
V
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
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