Exploration of piperidine-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with broad potency against resistant mutant viruses.
Further investigation of the recently reported piperidine-4-yl-aminopyrimidine class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out. Thus, preparation of a series of N-phenyl piperidine analogs resulted in the identification of 3-carboxamides as a particularly active series. Analogs such as 28 and 40 are very potent versus wild-type HIV-1 and a broad range of NNRTI-resistant mutant viruses. Synthesis, structure-activity relationship (SAR), clearance data, and crystallographic evidence for the binding motif are discussed.
Tang
Guozhi
G
Roche R&D Center China, Shanghai, China. gordon.tang@roche.com
Kertesz
Denis J
DJ
Yang
Minmin
M
Lin
Xianfeng
X
Wang
Zhanguo
Z
Li
Wentao
W
Qiu
Zongxing
Z
Chen
Junli
J
Mei
Jianghua
J
Chen
Li
L
Mirzadegan
Taraneh
T
Harris
Seth F
SF
Villaseñor
Armando G
AG
Fretland
Jennifer
J
Fitch
William L
WL
Hang
Julie Qi
JQ
Heilek
Gabrielle
G
Klumpp
Klaus
K
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D010880:Piperidines; D011743:Pyrimidines; C034821:4-aminopyrimidine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase