title: Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors.
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.
authors.affiliation: IRBM Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Rome, Italy. ester_muraglia@merck.com
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Olaf
authors.initials: O
authors.lastname: Kinzel
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
authors.forename: Benedetta
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Monica
authors.initials: M
authors.lastname: Donghi
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrara
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.forename: Federica
authors.initials: F
authors.lastname: Orvieto
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pescatore
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Odalys
authors.initials: O
authors.lastname: Gonzalez-Paz
authors.forename: Annalise
authors.initials: A
authors.lastname: Di Marco
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fiore
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fonsi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D008862:Microsomes, Liver / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C528852:9-(((dimethylamino)sulfonyl)(methyl)amino)-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-2-carboxamide; D000631:Aminopyridines; D001381:Azepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019428:HIV Integrase Inhibitors; C528853: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; D011744:Pyrimidinones; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1