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

[Display omitted] 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...

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Published in:Bioorganic & medicinal chemistry 2018-10, Vol.26 (18), p.5099-5117
Main Authors: Shinozuka, Tsuyoshi, Tsukada, Tomoharu, Fujii, Kunihiko, Tokumaru, Eri, Shimada, Kousei, Onishi, Yoshiyuki, Matsui, Yumi, Wakimoto, Satoko, Kuroha, Masanori, Ogata, Tsuneaki, Araki, Kazushi, Ohsumi, Jun, Sawamura, Ryoko, Watanabe, Nobuaki, Yamamoto, Hideki, Fujimoto, Kazunori, Tani, Yoshiro, Mori, Makoto, Tanaka, Jun
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Benzimidazole
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery
DS-6930
Female
Humans
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacology
Macaca fascicularis
Male
Models, Molecular
Molecular Structure
PPAR gamma - agonists
PPAR gamma - metabolism
PPARγ
Pyridines - administration & dosage
Pyridines - chemistry
Pyridines - pharmacology
Rats
Rats, Inbred F344
Rats, Zucker
Structure-Activity Relationship
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2018.09.005