Exploring the SAR of the β-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite

Abstract

In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.

Mycobacterial drug discovery

“…Lead optimisation efforts of this compound were pursued, but were rendered unsuccessful owing to the detection of a mutagenic aniline metabolite that could not be eliminated due to the limited structure–activity relationship (SAR) space. 79 This exemplifies the copious efforts and resources expended in drug discovery and provides one of an infinite number of reasons as to why promising drug candidates fail to progress through the drug discovery pipeline.…”

Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

“…A SAR study was designed to address primary metabolic stability of the compound as evidenced by relatively high clearance rates by microsomes while retaining or improving Mtb potency ( Abrahams et al., 2016 ; Kumar et al., 2018 ; Cunningham et al., 2020 ). The high metabolic turnover of 28 was ascribed to N -demethylation of indazole rendering an inactive compound ( Kumar et al., 2018 ).…”

“…GSK started their own lead optimization program based on the same indazole sulfonamide hit and its demethylated derivative was found to be equipotent to the initial hit ( Cunningham et al., 2020 ). This SAR study similarly found that the n -butyl group (C) was the favored moiety.…”

“…Progression of the indazole sulfonamide was, however, hindered by its embedded aniline moiety. The indazole amine was confirmed to be mutagenic and its formation in vivo was demonstrated by metabolite identification in treated rat urine ( Cunningham et al., 2020 ). To overcome this mutagenic potential, linkers to replace the nitrogen of the sulfonamide were generated but all were inactive.…”

Novel candidates in the clinical development pipeline for TB drug development and their synthetic approaches

“…GSK3011724A/GSK724 (DG167) 1 , a derivative of indazole sulphonamide, is undergoing early‐stage development of preclinical studies (Figure 2). It is being developed by GlaxoSmithKline and Rutgers, the State University of New Jersey (Cunningham et al., 2020). GSK3011724A is a small molecule active against Mycobacterium tuberculosis and identified from the aforementioned 228 phenotypic screening hits (Rebollo‐Lopez et al., 2015).…”