Novel fused pyrimidine and isoquinoline derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2016105532A1, WO2016105534A1 and WO2016105564A1

ABSTRACT

Introduction: In the three patent applications, the impact of changing the pyrimidine core of the rilpivirine (RPV) to a variety of alternative fused cores was explored, culminating in the identification of a series of conformationally restricted compounds with comparable potencies against WT and mutant HIV-1 strains with those of efavirenz (EFV) and RPV, and higher security in the Human Ether-a-go-go-Related Gene (hERG) assay.

Areas covered: The present review provides a fused pyrimidine and isoquinoline derivatives as potent HIV-1 NNRTIs, and highlights the conformational restriction strategies in the development of NNRTIs.

Expert opinion: The molecular docking analysis of the newly synthesized compounds maintain the classical horseshoe conformation and shares similar binding mode with RPV. The conformational restriction strategies have greatly accelerated the optimization of the DAPY NNRTIs and contribute to finding new chemical entities (NCEs) with favorable druggability.

KEYWORDS:

• HIV-1
• NNRTI
• diarylpyrimidine
• fused pyrimidine
• isoquinoline

Declaration of interest

The authors have no other 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 apart from those disclosed.

Additional information

Funding

Financial support from the National Natural Science Foundation of China (NSFC Nos. 81273354, 81573347), Key Project of NSFC for International Cooperation (Nos. 2014GSF118175, 30910103908), Young Scholars Program of Shandong University (YSPSDU, for P.Z.), the Science and Technology Development Project of Shandong Province (No. 2014GSF118175, 2014GSF118012), and Major Project of Science and Technology of Shandong Province (No. 2015ZDJS04001) is gratefully acknowledged​.