Discovery of DS-6930, a potent selective PPARγ modulator. Part II: Lead optimization

Abstract

Attempts were made to reduce the lipophilicity of previously synthesized compound (II) for the avoidance of hepatotoxicity. The replacement of the left-hand side benzene with 2-pyridine resulted in the substantial loss of potency. Because poor membrane permeability was responsible for poor potency in vitro, the adjustment of lipophilicity was examined, which resulted in the discovery of dimethyl pyridine derivative (I, DS-6930). In preclinical studies, DS-6930 demonstrated high PPARγ agonist potency with robust plasma glucose reduction. DS-6930 maintained diminished PPARγ-related adverse effects upon toxicological evaluation in vivo, and demonstrated no hepatotoxicity. Cofactor recruitment assay showed that several cofactors, such as RIP140 and PGC1, were significantly recruited, whereas several canonical factors was not affected. This selective cofactor recruitment was caused due to the distinct binding mode of DS-6930. The calcium salt, DS-6930b, which is expected to be an effective inducer of insulin sensitization without edema, could be evaluated clinically in T2DM patients.

The PPARΩPocket: Renewed Opportunities for Drug Development

“…Combined with the knowledge of their common capacity for stabilization of H12, the frequently observed undesirable effects of these ligands could be interpreted as signs of a mechanism-based toxicity. Furthermore, as findings from the study of PPARγ demonstrate that classical agonism is not required to attain therapeutically relevant transcriptional outcomes (see Section 5), recent ligand development targeting PPARγ has aimed at avoiding ligands that strongly stabilize H12 [97,[122][123][124][125][126][127]. And while such nonclassical ligands for PPARγ are becoming numerous (Section 5.3), there is a scarcity of similar ligands for PPARα and PPARβ/δ (see Sections 6.1 and 7.1).…”

Structure–Activity Relationship Studies of 3- or 4-Pyridine Derivatives of DS-6930

“…As expected, 1l displayed the same binding mode as DS-6930. 6 As no direct interaction with Tyr473 on helix 12 and the lipophilic interactions of dimethylpyridyl group were confirmed, these interactions relates for 1l to show partial agonist activity. A space around the 4′-positoin of benzimidazole ring surrounded by Phe264-Gly284-Arg288 was observed (Figure 2b).…”

“…6 The superior safety profile of DS-6930 was attributable to this distinct binding mode through the selective recruitment of cofactors. 6 We continued our exploration of structure−activity relationships (SARs) of this series of compounds to discover backup clinical candidates for DS-6930. Herein, we report SAR studies of 3-or 4-pyridines to identify novel PPARγ intermediate agonist 3g (DS19161384), which demonstrated robust pharmacological efficacy with excellent DMPK properties in preclinical studies.…”

“…Such a conventional approach led to the discovery of DS-6930 ( III , Figure ). DS-6930 demonstrated potent plasma glucose (PG) reduction with fewer PPARγ-related adverse effects than rosiglitazone in preclinical studies . Based on the cocrystal structure of III bound to PPARγ ligand binding domain (LBD), the avoidance of direct interactions with Tyr473 on helix 12 and the additional lipophilic interactions of dimethylpyridyl group are suggested to be related to the intermediate agonist activity of DS-6930 .…”

“… DS-6930 demonstrated potent plasma glucose (PG) reduction with fewer PPARγ-related adverse effects than rosiglitazone in preclinical studies . Based on the cocrystal structure of III bound to PPARγ ligand binding domain (LBD), the avoidance of direct interactions with Tyr473 on helix 12 and the additional lipophilic interactions of dimethylpyridyl group are suggested to be related to the intermediate agonist activity of DS-6930 . The superior safety profile of DS-6930 was attributable to this distinct binding mode through the selective recruitment of cofactors .…”