Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors.
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.
Muraglia
Ester
E
IRBM Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Rome, Italy. ester_muraglia@merck.com
Kinzel
Olaf
O
Gardelli
Cristina
C
Crescenzi
Benedetta
B
Donghi
Monica
M
Ferrara
Marco
M
Nizi
Emanuela
E
Orvieto
Federica
F
Pescatore
Giovanna
G
Laufer
Ralph
R
Gonzalez-Paz
Odalys
O
Di Marco
Annalise
A
Fiore
Fabrizio
F
Monteagudo
Edith
E
Fonsi
Massimiliano
M
Felock
Peter J
PJ
Rowley
Michael
M
Summa
Vincenzo
V
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
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