Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: improving cell based activity by the quaternarization of a chiral center.
In the context of HIV-integrase, dihydroxypyrimidine and N-methyl pyrimidone inhibitors the cellular activity of this class of compounds has been optimized by the introduction of a simple methyl substituent in the alpha-position of the C-2 side chains. Enhanced passive membrane permeability has been identified as the key factor driving the observed cell-based activity improvement. The rat PK profile of the alpha-methyl derivative 26a was also improved over its des-methyl exact analog.
Nizi
Emanuela
E
Department of Medicinal Chemistry, IRBM-Merck Research Laboratories Rome, Pomezia, Italy. emanuela_nizi@merck.com
Orsale
Maria Vittoria
MV
Crescenzi
Benedetta
B
Pescatore
Giovanna
G
Muraglia
Ester
E
Alfieri
Anna
A
Gardelli
Cristina
C
Spieser
Stéphane A H
SA
Summa
Vincenzo
V
D000818:Animals; D002463:Cell Membrane Permeability; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats
D019428:HIV Integrase Inhibitors; D011743:Pyrimidines; D011744:Pyrimidinones; D019427:HIV Integrase