Pyrazole NNRTIs 3: optimisation of physicochemical properties.
Our efforts to reduce overall lipophilicity and increase ligand-lipophilicity efficiency (LLE) by modification of the 3- and 5-substituents of pyrazole 1, a novel non-nucleoside HIV reverse transcriptase inhibitor (NNRTI) prototype were unsuccessful. In contrast replacement of the substituted benzyl group with corresponding phenylthio or phenoxy groups resulted in marked improvements in potency, ligand efficiency (LE) and LLE.
Mowbray
Charles E
CE
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT 13 9NJ, UK. Charles.Mowbray@Pfizer.com
Corbau
Romuald
R
Hawes
Michael
M
Jones
Lyn H
LH
Mills
James E
JE
Perros
Manos
M
Selby
Matthew D
MD
Stupple
Paul A
PA
Webster
Rob
R
Wood
Anthony
A
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055598:Chemical Phenomena; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D019380:Anti-HIV Agents; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C031280:pyrazole; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase