title: Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: improving cell based activity by the quaternarization of a chiral center.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, IRBM-Merck Research Laboratories Rome, Pomezia, Italy. emanuela_nizi@merck.com
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Orsale
authors.forename: Benedetta
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pescatore
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Anna
authors.initials: A
authors.lastname: Alfieri
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
authors.forename: Stéphane A H
authors.initials: SA
authors.lastname: Spieser
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
mesh_terms: 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
chemical_list: D019428:HIV Integrase Inhibitors; D011743:Pyrimidines; D011744:Pyrimidinones; D019427:HIV Integrase