Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents.

Abstract

We previously reported that (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKA y . This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-g g. We expanded on the structure-activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPARg g. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARg g, were tested using KKA y mice. Among these compounds, (E)-4-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation.

Studies on Non-Thiazolidinedione Antidiabetic Agents. 3. Preparation and Biological Activity of the Metabolites of TAK-559

“…plays the key role for in vivo glucose and lipid lowering activities, rather than its metabolites (2)(3)(4)(5). However, it is well known that the in vivo activities of compounds can be significantly different from their in vitro activities.…”

“…2) TAK-559 also exhibits marked glucose and lipid lowering activities in insulin-resistant animal models, KKA y mice and Wistar fatty rats, 2,[10][11][12][13] and is under clinical trials. Metabolites M-I, M-II, M-III and M-IV were found during preclinical and clinical studies on TAK-559 (1), and their proposed structures are shown in Chart 1.…”

“…Friedel-Crafts acylation of 6a-b gave aryl ketones 7a-b, of which the methoxy groups were converted into hydroxy groups using boron tribromide to yield 8a-b. Reactions of 8a-b with 9 2) gave aldoximes, which were hydrolyzed to afford 2 and 3.…”

“…Selective removal of the methoxymethyl group of 13 was achieved using bromotrimethylsilane to give alcohol 14. Compound 14 was reacted with methanesulfonyl chloride, then coupled with 15 2) to provide 16. Removal of the tert-butyldiphenylsilyl group of 16 and subsequent hydrolysis of the ester group gave the desired compound 4.…”

“…To confirm the structures and to study the biological properties of the metabolites, compounds 2-5 (Charts 2-4) were synthesized and their biological activities were evaluated by both in vitro and in vivo experiments. Analytical high-performance liquid chromatography (HPLC) and mass spectroscopy (MS) of isolated metabolites (M-I, M-II, M-III, M-IV) and synthesized compounds (2)(3)(4)(5) were shown to be identical respectively (data not shown). Transactivation activities of compounds 1-5 for human PPAR subtypes were examined using in vitro experiments, and the glucose and lipid lowering effects of the compounds were evaluated in Wistar fatty rats using in vivo experiments.…”