Synthesis and antiviral activity of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV integrase inhibitors.
The medicinal chemistry and structure-activity relationships for a novel series of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV-integrase inhibitors are disclosed. Substituent effects were evaluated at the N-1, C-3, and 7-benzyl positions of the naphthyridinone ring system. Low nanomolar IC(50) values were achieved in an HIV-integrase strand transfer assay with both carboxylic ester and carboxamide groups at C-3. More importantly, several carboxamide congeners showed potent antiviral activity in cellular assays. A 7-benzyl substituent was found to be critical for potent enzyme inhibition, and an N-(2-methoxyethyl)carboxamide moiety at C-3 significantly reduced plasma protein binding effects in vitro. Pharmacokinetic data in rats for one carboxamide analogue demonstrated oral bioavailability and reasonable in vivo clearance.
GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. eric.e.boros@gsk.com
Eric E
EE
Boros
Cynthia E
CE
Edwards
Scott A
SA
Foster
Masahiro
M
Fuji
Tamio
T
Fujiwara
Edward P
EP
Garvey
Pamela L
PL
Golden
Richard J
RJ
Hazen
Jerry L
JL
Jeffrey
Brian A
BA
Johns
Takashi
T
Kawasuji
Ryuichi
R
Kiyama
Cecilia S
CS
Koble
Noriyuki
N
Kurose
Wayne H
WH
Miller
Angela L
AL
Mote
Hitoshi
H
Murai
Akihiko
A
Sato
James B
JB
Thompson
Mark C
MC
Woodward
Tomokazu
T
Yoshinaga
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D004952:Esters / Q000737:chemistry; D006678:HIV / Q000187:drug effects / Q000201:enzymology*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D002264:Carboxylic Acids; D004952:Esters; D019428:HIV Integrase Inhibitors; D009287:Naphthyridines; D019427:HIV Integrase