TY - JOUR
T1 - Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase
AU - Zhang, Daoguang
AU - Debnath, Bikash
AU - Yu, Shenghui
AU - Sanchez, Tino Wilson
AU - Christ, Frauke
AU - Liu, Yang
AU - Debyser, Zeger
AU - Neamati, Nouri
AU - Zhao, Guisen
N1 - Funding Information:
The work in GZ laboratory was supported by a grant from the National Natural Science Foundation of China (Grant Numbers: 20872082 and 21272140 ). The work in NN and ZD laboratories were supported by funds from an NIH/NIAID ( R21 AI081610 ) grant. TWS was funded by the NIH F31 ( AI082942-01 ) and CHRP ( D08-USC-321 ) awards.
Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.
AB - Raltegravir (RAL) is a first clinically approved integrase (IN) inhibitor for the treatment of HIV but rapid mutation of the virus has led to chemo-resistant strains. Therefore, there is a medical need to develop new IN inhibitors to overcome drug resistance. At present, several IN inhibitors are in different phases of clinical trials and few have been discontinued due to toxicity and lack of efficacy. The development of potent second-generation IN inhibitors with improved safety profiles is key for selecting new clinical candidates. In this article, we report the design and synthesis of potent 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide analogues as second-generation IN inhibitors. These compounds satisfy two structural requirements known for potent inhibition of HIV-1 IN catalysis: a metal chelating moiety and a hydrophobic functionality necessary for selectivity against the strand transfer reaction. Most of the new compounds described herein are potent and selective for the strand transfer reaction and show antiviral activity in cell-based assays. Furthermore, this class of compounds are drug-like and suitable for further optimization and preclinical studies.
KW - 5-Hydroxy-6-oxo-1,6-dihydropyrimidine analogues
KW - HIV-1 integrase inhibitors
KW - INSTIs
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U2 - 10.1016/j.bmc.2014.07.036
DO - 10.1016/j.bmc.2014.07.036
M3 - Article
C2 - 25150089
AN - SCOPUS:84907535228
SN - 0968-0896
VL - 22
SP - 5446
EP - 5453
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 19
ER -