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    • Having identified initial leads and further lead optimizatio

    2021-10-16

    Having identified initial leads and (), further lead optimization was initiated on B- and C-rings to afford compounds with improved potency. Initial set of substituted imidazole-biphenyl-carboxylic 10Panx derivatives – and () were evaluated for GSNOR potency. Among this, fluoro, methyl, chloro and CF substituted C-ring carboxylic acid analogs – revealed only marginal improvement in GSNOR potency (IC: 29–38 nM range), whereas compound (IC: 20 nM) having methyl substituent in the B-ring unveiled 3-fold improvement in potency compared to initial lead (IC: 62 nM). Next, among the substituted pyridine derived biaryl carboxylic acids – assessed for GSNOR potency, only methyl substituted pyridine biaryl compounds and exhibited GSNOR potency comparable to non-pyridine derivatives –, whereas other pyridine derived analogs and showed substantial loss of potency. Though few GSNOR inhibitors with acid functionality () were obtained in comparable GSNOR potency to N6022 () and N91115 (), these compounds were not considered for further development as oral drug, due to potential formation of acyl glucuronide through phase-II metabolism., Hence, the focus was shifted to various tetrazole analogs –, –, –, – and , which are bioisosteric replacement of carboxylic acid in which expected to offer enhanced potency and improved pharmacokinetic (PK) properties (). Though, initial tetrazole lead (IC: 22 nM) has comparable GSNOR potency to clinical candidates [N6022 () and N91115 ()], it had high inhibition against major CYP isoforms tested (1A2, 2D6, 3A4, 2C9 and 2C19) and low liver microsomal stability in mice (∼30% remaining after 1 h incubation). Therefore, it was presumed that diverse substitution and nitrogen insertion on the biaryl ring would probably deliver enhanced potency, reduced CYP liability, adequate metabolic stability and an improved physicochemical properties. In order to address CYP liability on compound , 2-methylimidazole as A-ring was introduced and that led to compound (IC: 97 nM), which revealed 5-fold lower GSNOR potency in comparison to compound . However, the CYP inhibition of compound was significantly low (<33% @ 10 µM to major CYP isoforms tested, ) in addition to high metabolic stability in human, rat and mouse liver microsomes. Next, we focused our attention on the B- and C-ring modification of compound to afford improved GSNOR potency. Among the many C-ring substituted compounds (–) tested for GSNOR potency, -substituted chloro biphenyl derivative (IC: 9.2 nM) provided improvement in potency compared to initial lead . On the other hand, bulky CF-substituted C-ring compound (IC: 39 nM) gave one-fold lower GSNOR potency and all other compounds exhibited marginally lower potency () compared to compound . Further, substitution on B- and B-C ring yielded compounds – revealed enhanced GSNOR potency compared to compound . Particularly, ethyl substituted B-ring compound (IC: 6.1 nM) showed greter than 3-fold higher potency and its corresponding 2-methylimidazole A-ring analog (IC: 24 nM) exhibited comparable potency to lead and noticeably reduced potency than . The lower potency of 2-methylimidazole derived A-ring analogs , and further confirmed that only imidazole is well tolerated in the A-ring to hold onto GSNOR potency (). Compounds and (ICs: 12 nM and 11 nM) having substitution on both B- and C-rings afforded enhanced potency than compound and as comparable to compound (IC: 9.2 nM), respectively. Next set of compounds –, – and having nitrogen incorporated in the B-ring along with various substituents either in B-ring or C-ring and or B-C ring were evaluated for GSNOR potency. Compounds – having nitrogen in the B-ring and methyl, chloro-substituents in C-ring exhibited decreased enzyme potency (). Specifically, compound (IC: 308 nM), which is a nitrogen inserted B-ring analog of compound (IC: 9.2 nM) revealed 35-fold drop in GSNOR potency. Further, compounds and having Cl, and CH-substituents as well as nitrogen in the B-ring provided potency similar to lead . Among the di-substituted B-C ring compounds including nitrogen in the B-ring (–) tested for GSNOR potency, compound having chloro- and methyl in the -position of biphenyl B-C ring revealed greter than 100-fold diminished potency. Other two di-substituted pyridine derived biaryl compounds (, ) having smaller fluorine in the -position of biaryl C-ring, and methyl, chlorine in the -position of nitrogen inserted B-ring unveiled potency similar to lead . The probable reason for inferior potency of compound would be due to non-planar geometry of the molecule because of bis-ortho substitution on the B-C ring of biaryl. Further, nitrogen inserted B-ring compounds (, and ) having substitution on the B-ring (ethyl and cyclopropyl) showed reduced potency (IC: >60 nM) and precisely pyridine biaryl analog (IC: 66 nM) revealed 10-fold diminished GSNOR potency compared to structurally similar analog (IC: 6.1 nM). Overall, most of the pyridine derived biaryl analogs exhibited decreased GSNOR potency in comparison to simple biphenyl derivatives except few (–) which retained potency similar to lead ().