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.
Kertesz
Denis J
DJ
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. deniskertesz@comcast.net
Brotherton-Pleiss
Christine
C
Yang
Minmin
M
Wang
Zhanguo
Z
Lin
Xianfeng
X
Qiu
Zongxing
Z
Hirschfeld
Donald R
DR
Gleason
Shelley
S
Mirzadegan
Taraneh
T
Dunten
Pete W
PW
Harris
Seth F
SF
Villaseñor
Armando G
AG
Hang
Julie Qi
JQ
Heilek
Gabrielle M
GM
Klumpp
Klaus
K
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