Novel nevirapine-like inhibitors with improved activity against NNRTI-resistant HIV: 8-heteroarylthiomethyldipyridodiazepinone derivatives.
A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes.
Yoakim
C
C
Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research & Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. cyoakim@lav.boehringer-ingelheim.com
Bonneau
P R
PR
Déziel
R
R
Doyon
L
L
Duan
J
J
Guse
I
I
Landry
S
S
Malenfant
E
E
Naud
J
J
Ogilvie
W W
WW
O'Meara
J A
JA
Plante
R
R
Simoneau
B
B
Thavonekham
B
B
Bös
M
M
Cordingley
M G
MG
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D019829:Nevirapine / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D001381:Azepines; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; C023666:pyridine