N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase.
A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. mmitchell@gilead.com
Michael L
ML
Mitchell
Jong Chan
JC
Son
Ill Young
IY
Lee
Chong-Kyo
CK
Lee
Hae Soo
HS
Kim
Hongyan
H
Guo
Jianhong
J
Wang
Jaclyn
J
Hayes
Michael
M
Wang
Amber
A
Paul
Eric B
EB
Lansdon
James M
JM
Chen
Gene
G
Eisenberg
Romas
R
Geleziunas
Lianhong
L
Xu
Choung U
CU
Kim
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004285:Dogs; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008861:Microsomes / Q000378:metabolism; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D006571:Heterocyclic Compounds; D050505:Mutant Proteins; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D013941:Thymine