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.
Discovery Chemistry, Sandwich Laboratories, Pfizer Global Research and Development, Ramsgate Road, Kent, UK.
Lyn H
LH
Jones
Gill
G
Allan
Romuald
R
Corbau
Duncan
D
Hay
Donald S
DS
Middleton
Charles E
CE
Mowbray
Sandra D
SD
Newman
Manos
M
Perros
Amy
A
Randall
Hannah
H
Vuong
Rob
R
Webster
Mike
M
Westby
David
D
Williams
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