Pyrazolo[1,5-a]pyrimidine-based macrocycles as novel HIV-1 inhibitors: a patent evaluation of WO2015123182

ABSTRACT

The emergence of drug resistance in Combination Antiretroviral Therapy (cART) confirms a continuing need to investigate novel HIV-1 inhibitors with unexplored mechanisms of action. Recently, a series of pyrazolopyrimidine-based macrocyclic compounds were reported as inhibitors of HIV-1 replication disclosed in the patent WO2015123182. Most of the disclosed compounds possessed in vitro antiviral potency in single-digit nanomolar range, which were determined by MT-2 cell assay. Then, the structural diversity, pharmacophore similarity of HIV-1 IN-LEDGF/p75 inhibitors, and implications for drug design were analyzed. In the end of this article, a glimpse of some macrocycles as potent antiviral agents (drug candidates) was provided. Some strategies and technologies enabling macrocycle design were also described. We expect that further development of these macrocyclic compounds will offer new anti-HIV-1 drug candidates.

KEYWORDS:

• HIV-1
• AIDS
• drug resistance
• cART
• drug design
• macrocycle
• protein-protein interactions

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors were supported by the National Natural Science Foundation of China (NSFC) Projects for International Cooperation and Exchange program (No. 81420108027), by the Science and Technology Major Project of Shandong Province (Major key technology, No. 2015ZDJS04001), and by the NSFC (No. 81273354 and 81573347).