Structure-based lead optimization to improve antiviral potency and ADMET properties of phenyl-1H-pyrrole-carboxamide entry inhibitors targeted to HIV-1 gp120

Abstract

We are continuing our concerted effort to optimize our first lead entry antagonist, NBD-11021, which targets the Phe43 cavity of the HIV-1 envelope glycoprotein gp120, to improve antiviral potency and ADMET properties. In this report, we present a structure-based approach that helped us to generate working hypotheses to modify further a recently reported advanced lead entry antagonist, NBD-14107, which showed significant improvement in antiviral potency when tested in a single-cycle assay against a large panel of Env-pseudotyped viruses. We report here the synthesis of twenty-nine new compounds and evaluation of their antiviral activity in a single-cycle and multi-cycle assay to derive a comprehensive structure-activity relationship (SAR). We have selected three inhibitors with the high selectivity index for testing against a large panel of 55 Env-pseudotyped viruses representing a diverse set of clinical isolates of different subtypes. The antiviral activity of one of these potent inhibitors, 55 (NBD-14189), against some clinical isolates was as low as 63 nM. We determined the sensitivity of CD4-binding site mutated-pseudoviruses to these inhibitors to confirm that they target HIV-1 gp120. Furthermore, we assessed their ADMET properties and compared them to the clinical candidate attachment inhibitor, BMS-626529. The ADMET data indicate that some of these new inhibitors have comparable ADMET properties to BMS-626529 and can be optimized further to potential clinical candidates.

Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120

“…When we attempted to introduce the 1,3-benzodioxole moiety in the oxalamide-containing NBD-14108 and NBD-14109, the antiviral activity was completely lost, unlike what was observed by Ohashi et al [7a] . We attempted to replace the 1,3-benzodioxole moiety with its bioisostere, 2,1,3-benzothiadiazole [5] .…”

“…Previously, we reported that some specific amino acid substitutions in the CD4‐binding site of the ENV gp120 rendered the mutant virus resistant to the NBD compounds, but S375H, S375W, and S375Y mutant viruses were not . In this study, we tested NBD‐14110 against the mutant pseudovirus HIV‐1 HXB2 carrying amino acid substitution S375Y or S375W in the ENV gp120 region.…”

“…Aryl bromides 13 and 22 were prepared by using published procedures . Protected amines 37 , 39 , 40 , 41 , and 42 and protected thiazoles 31 and 34 were prepared as described previously . Two protected amines, 33 and 36 , with the gem‐dimethyl moiety were prepared using 1,2‐addition of thiazolyl anions of the two enantiopure imines 30 , as per Scheme .…”

“…We introduced the amino acid substitutions S375Y and S375W into the pHXB2‐Env expression vector by site‐directed mutagenesis (Stratagene) using mutagenic oligonucleotides as previously described . The ENV plasmids carrying the above amino acid substitutions were sequenced and analyzed with the Geneious R8 software (Biomatters, New Zealand).…”

“…The chemical structure of NBD-556, YYA-021 [6] , and our next-generation lead compounds [1a, 4, 7] .…”