Optimization of 5-aryloxyimidazole non-nucleoside reverse transcriptase inhibitors.
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their vulnerability to mutations in the allosteric binding site of reverse transcriptase that can result in the development of a resistant virus. Herein we present the optimization of a series of 5-aryloxy imidazoles, which possess a balanced pharmacological profile against both wild-type enzyme and the clinically relevant mutations K103N and Y181C. Subtle structural changes were used to probe structure-activity relationships relating to both potency and metabolic stability, which led to an imidazole derivative with an impressive overall profile.
Jones
Lyn H
LH
Discovery Chemistry, Sandwich Laboratories, Pfizer Global Research and Development, Ramsgate Road, Kent, UK.
Allan
Gill
G
Corbau
Romuald
R
Hay
Duncan
D
Middleton
Donald S
DS
Mowbray
Charles E
CE
Newman
Sandra D
SD
Perros
Manos
M
Randall
Amy
A
Vuong
Hannah
H
Webster
Rob
R
Westby
Mike
M
Williams
David
D
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000495:Allosteric Site; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013457:Sulfur Compounds / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; D013457:Sulfur Compounds; D054303:HIV Reverse Transcriptase; C433874:capravirine