Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors

Ester Muraglia; Olaf Kinzel; Cristina Gardelli; Benedetta Crescenzi; Monica Donghi; Marco Ferrara; Emanuela Nizi; Federica Orvieto; Giovanna Pescatore; Ralph Laufer; Odalys Gonzalez-Paz; Annalise Di Marco; Fabrizio Fiore; Edith Monteagudo; Massimiliano Fonsi; Peter J Felock; Michael Rowley; Vincenzo Summa

doi:10.1021/jm701164t

Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors

J Med Chem. 2008 Feb 28;51(4):861-74. doi: 10.1021/jm701164t. Epub 2008 Jan 25.

Authors

Ester Muraglia¹, Olaf Kinzel, Cristina Gardelli, Benedetta Crescenzi, Monica Donghi, Marco Ferrara, Emanuela Nizi, Federica Orvieto, Giovanna Pescatore, Ralph Laufer, Odalys Gonzalez-Paz, Annalise Di Marco, Fabrizio Fiore, Edith Monteagudo, Massimiliano Fonsi, Peter J Felock, Michael Rowley, Vincenzo Summa

Affiliation

¹ IRBM Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Rome, Italy. ester_muraglia@merck.com

PMID: 18217703
DOI: 10.1021/jm701164t

Abstract

HIV integrase is one of the three enzymes encoded by HIV genome and is essential for viral replication, but integrase inhibitors as marketed drugs have just very recently started to emerge. In this study, we show the evolution from the N-methylpyrimidinone structure to bicyclic pyrimidinones. Introduction of a suitably substituted amino moiety modulated the physical-chemical properties of the molecules and conferred nanomolar activity in the inhibition of spread of HIV-1 infection in cell culture. An extensive SAR study led to sulfamide (R)- 22b, which inhibited the strand transfer with an IC50 of 7 nM and HIV infection in MT4 cells with a CIC95 of 44 nM, and ketoamide (S)- 28c that inhibited strand transfer with an IC50 of 12 nM and the HIV infection in MT4 cells with a CIC95 of 13 nM and exhibited a good pharmacokinetic profile when dosed orally to preclinical species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Aminopyridines / chemical synthesis*
Aminopyridines / pharmacokinetics
Aminopyridines / pharmacology
Animals
Azepines / chemical synthesis*
Azepines / pharmacokinetics
Azepines / pharmacology
Biological Availability
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line
Dogs
HIV Integrase / genetics
HIV Integrase / metabolism*
HIV Integrase Inhibitors / chemical synthesis*
HIV Integrase Inhibitors / pharmacokinetics
HIV Integrase Inhibitors / pharmacology
HIV-1 / drug effects
Humans
Macaca mulatta
Microsomes, Liver / metabolism
Pyrimidinones / chemical synthesis*
Pyrimidinones / pharmacokinetics
Pyrimidinones / pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship

Substances

9-(((dimethylamino)sulfonyl)(methyl)amino)-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-2-carboxamide
Aminopyridines
Azepines
Bridged Bicyclo Compounds, Heterocyclic
HIV Integrase Inhibitors
N-(2-(((4-fluorobenzyl)amino)carbonyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido(1,2-a)azepin-10-yl)-N,N',N'-trimethylethanediamide
Pyrimidinones
HIV Integrase
p31 integrase protein, Human immunodeficiency virus 1