Details

Autor(en) / Beteiligte

• Genin, Michael J
• Biles, Carolyn
• Keiser, Barb J
• Poppe, Susan M
• Swaney, Steven M
• Tarpley, W. Gary
• Yagi, Yoshihiko
• Romero, Donna L

Titel

Novel 1,5-Diphenylpyrazole Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors with Enhanced Activity versus the Delavirdine-Resistant P236L Mutant:  Lead Identification and SAR of 3- and 4-Substituted Derivatives

Ist Teil von

• Journal of medicinal chemistry, 2000-03, Vol.43 (5), p.1034-1040

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2000

Quelle

MEDLINE

Beschreibungen/Notizen

• Through computationally directed broad screening, a novel 1,5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC50 = 2.3 μM) and delavirdine-resistant P236L (IC50 = 1.1 μM) reverse transcriptase (RT). Also, PNU-32945 has an ED50 for inhibition of viral replication in cell cultures of 0.1 μM and was shown to be noncytotoxic with a CC50 > 10 μM. Structure−activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC50 = 0.65 μM), whereas it is essentially inactive versus the wild-type enzyme (IC50 > 50 μM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.