Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: improving cell based activity by the quaternarization of a chiral center

Emanuela Nizi; Maria Vittoria Orsale; Benedetta Crescenzi; Giovanna Pescatore; Ester Muraglia; Anna Alfieri; Cristina Gardelli; Stéphane A H Spieser; Vincenzo Summa

doi:10.1016/j.bmcl.2009.06.091

Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: improving cell based activity by the quaternarization of a chiral center

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4617-21. doi: 10.1016/j.bmcl.2009.06.091. Epub 2009 Jun 27.

Authors

Emanuela Nizi¹, Maria Vittoria Orsale, Benedetta Crescenzi, Giovanna Pescatore, Ester Muraglia, Anna Alfieri, Cristina Gardelli, Stéphane A H Spieser, Vincenzo Summa

Affiliation

¹ Department of Medicinal Chemistry, IRBM-Merck Research Laboratories Rome, Pomezia, Italy. [email protected]

PMID: 19616948
DOI: 10.1016/j.bmcl.2009.06.091

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.

MeSH terms

Animals
Cell Membrane Permeability
HIV Integrase / chemistry*
HIV Integrase / metabolism
HIV Integrase Inhibitors / chemical synthesis
HIV Integrase Inhibitors / chemistry*
HIV Integrase Inhibitors / pharmacokinetics
Humans
Protein Binding
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry*
Pyrimidinones / pharmacokinetics
Rats

Substances

HIV Integrase Inhibitors
Pyrimidines
Pyrimidinones
HIV Integrase