Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses.
An analysis of the binding motifs of known HIV-1 non-nucleoside reverse transcriptase inhibitors has led to discovery of novel piperidine-linked aminopyrimidine derivatives with broad activity against wild-type as well as drug-resistant mutant viruses. Notably, the series retains potency against the K103N/Y181C and Y188L mutants, among others. Thus, the N-benzyl compound 5k has a particularly attractive profile. Synthesis and SAR are presented and discussed, as well as crystal structures relating to the binding motifs.
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. deniskertesz@comcast.net
Denis J
DJ
Kertesz
Christine
C
Brotherton-Pleiss
Minmin
M
Yang
Zhanguo
Z
Wang
Xianfeng
X
Lin
Zongxing
Z
Qiu
Donald R
DR
Hirschfeld
Shelley
S
Gleason
Taraneh
T
Mirzadegan
Pete W
PW
Dunten
Seth F
SF
Harris
Armando G
AG
Villaseñor
Julie Qi
JQ
Hang
Gabrielle M
GM
Heilek
Klaus
K
Klumpp
D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase