Studies on antidiabetic agents. II. Synthesis of 5-(4-(1-methylcyclohexylmethoxy)-benzyl)thiazolidine-2,4-dione (ADD-3878) and its derivatives.

Sohda, Takashi; Mizuno, Katsutoshi; Imamiya, Eiko; Sugiyama, Yasuo; Fujita, Toshio; Kawamatsu, Yutaka

doi:10.1248/cpb.30.3580

Cited by 171 publications

(67 citation statements)

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“…[5][6][7] They found that ciglitazone had both antilipidemic and antihyperglycemic effects. Lehman and colleagues were subsequently the first to identify peroxisome proliferator-activated receptor g (PPARg) as a molecular target for TZDs.…”

Section: Pparc Is the Primary Target Transcription Factor For Tzdsmentioning

confidence: 99%

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

2005

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The potent insulin-sensitizing effects of peroxisome proliferator-activated receptor g (PPARg) agonists are well established. However, it is still a matter of intense debate as to which tissue(s) represent the most critical sites of action for PPARg agonists, and what the relevant target genes are that ultimately mediate the improvements in insulin sensitivity. The cell type with the highest levels of PPARg is the adipocyte, and as such the adipocyte is an excellent candidate cell to look for critical mediators of PPARg agonist action. Adiponectin, an adipocyte-specific secretory protein, is upregulated in response to PPARg agonist exposure, and its serum levels consequently increase significantly. Genetic, pharmacological and clinical studies have demonstrated potent insulin-sensitizing effects of adiponectin. Here, we summarize the evidence that implicates adiponectin as a critical mediator of PPARg-agonist-mediated improvements in insulin sensitivity, particularly in the context of PPARg-agonistmediated enhancements of hepatic insulin sensitivity.

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Section: Pparc Is the Primary Target Transcription Factor For Tzdsmentioning

confidence: 99%

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

2005

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“…During the last decade, an exhaustive search for novel agents based on the TZD ciglitazone (Shoda et al 1982) has yielded three commercially marketed drugs: pioglitazone (Mosome et al 1991), rosiglitazone (Cantello et al 1994) and troglitazone. Troglitazone also lowers the excess androgens in women with PCOS (Azziz et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Cinnamic acid based thiazolidinediones inhibit human P450c17 and 3beta-hydroxysteroid dehydrogenase and improve insulin sensitivity independent of PPARgamma agonist activity

Arlt¹,

Neogi²,

Gross³

et al. 2004

Journal of Molecular Endocrinology

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Thiazolidinediones improve insulin sensitivity in type 2 diabetes mellitus by acting as peroxisome proliferator-associated receptor gamma (PPAR ) agonists, and decrease circulating androgen concentrations in polycystic ovary syndrome by unknown mechanisms. Some thiazolidinediones directly inhibit the steroidogenic enzymes P450c17 and 3 -hydroxysteroid dehydrogenase type II (3 HSDII) by distinct mechanisms. We synthesized five novel thiazolidinediones, CLX-M1 to -M5 by linking a 2,4-thiazolidinedione moiety to a substituted -phenyl cinnamic acid previously shown to have glucose-lowering effects. Using yeast microsomes expressing human P450c17 and 3 HSDII we found that cinnamic acid methyl esters with a double bond in the thiazolidinedione core structure (M3, M5) were stronger inhibitors of P450c17 than methyl esters with the conventional core (M1, M4). These four compounds inhibited 3 HSDII equally well, while the free cinnamic acid analog (M2) did not inhibit either enzyme. Thus, the inhibition of P450c17 and 3 HSDII by these novel thiazolidinediones reveals structure-activity relationships independent of PPAR transactivation. PPAR transactivation was moderate (M1), weak (M2, M3) or even absent (M4, M5). While the PPAR agonist activity of M1 was only 3% of that of rosiglitazone, both increased glucose uptake by 3T3-L1 adipocytes and reduced serum glucose levels in ob/ob and db/db mice to a similar extent. The similar glucose-lowering effects of M1 and rosiglitazone, despite their vast differences in PPAR agonist activity, suggests these two actions may occur by separate mechanisms.

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“…Friedel-Crafts acylation of substituted benzenes with ethyl oxalyl chloride gave phenylglyoxylates (14), which were treated with hydroxylamine to provide oximes (11d, e) as a mixture of E-and Z-isomers (Chart 3). These isomers were easily separated by column chromatography.…”

Section: Chemistrymentioning

confidence: 99%

“…The prototypical 2,4-thiazolidinedione, ciglitazone (1) 14) (Chart 1) was discovered by our company, and has antihyperglycemic activity in insulin-resistant animal models, KKA y mice 15) and Wistar fatty rats, 16) but no effect in insulin-deficient animal models of diabetes. 17,18) During structure-activity relationship studies on 2,4-thiazolidinediones and related compounds, we discovered highly potent compounds, such as pioglitazone (2), 19) and AD-5061 (3) 20) (Chart 1).…”

mentioning

confidence: 99%

Studies on Non-Thiazolidinedione Antidiabetic Agents. 1. Discovery of Novel Oxyiminoacetic Acid Derivatives.

Imamiya

Momose

et al. 2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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Studies on antidiabetic agents. II. Synthesis of 5-(4-(1-methylcyclohexylmethoxy)-benzyl)thiazolidine-2,4-dione (ADD-3878) and its derivatives.

Cited by 171 publications

References 0 publications

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

Adiponectin: a relevant player in PPARγ-agonist-mediated improvements in hepatic insulin sensitivity?

Cinnamic acid based thiazolidinediones inhibit human P450c17 and 3beta-hydroxysteroid dehydrogenase and improve insulin sensitivity independent of PPARgamma agonist activity

Studies on Non-Thiazolidinedione Antidiabetic Agents. 1. Discovery of Novel Oxyiminoacetic Acid Derivatives.

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