Novel thiazolidine-2,4-diones as potent euglycemic agents.

Hulin, Bernard; Clark, David A.; Goldstein, Solomon; McDermott, Ruth E.; Dambek, Paul J.; Kappeler, W. H.; Lamphere, Charles H.; Lewis, Dana; Rizzi, James P.

doi:10.1021/jm00088a022

Cited by 77 publications

(37 citation statements)

References 1 publication

(7 reference statements)

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“…Catalytic dehalogenation of 13 and following protection of the amine with the Boc group afforded ethyl (S)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (14). Etherification of 14 with methanesulfonate 15 9,16) in the presence of K 2 CO 3 afforded 16. The Boc group of 16 was removed with HCl/HCO 2 H, affording 17.…”

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confidence: 99%

Synthesis and Biological Evaluation of (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: A Novel Series of PPAR.GAMMA. Agonists

Azukizawa

Kasai

Takahashi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Peroxisome proliferators-activated receptors (PPARs) are a subfamily of nuclear hormone receptors, which are ligandactivated transcription factors. There are three subtypes of PPAR: PPARa expressed in the liver and related to fatty acid metabolism, PPARg expressed in adipocytes and playing a role in its differentiation, and PPARd expressed in most cell types and involved in dyslipidemia, cancer and the central nervous system; therefore, PPARs have been focused on as a potential target for metabolic diseases such as diabetes, dyslipidemia and atherosclerosis.1-3) Fibrates such as clofibrate, bezafibrate and fenofibrate, which have been long and widely used as anti-hyperlipidemic drugs, are known to exert their effect via activation of PPARa. Thiazolidinedione derivatives (glitazones), such as pioglitazone and rosiglitazone, known as anti-diabetic drugs, activate PPARg and enhance insulin sensitivity. 4,5) Thiazolidinedione derivatives cause edema, increase the risk of weight gain and congestive heart failure, and rarely show hepatotoxicity.6,7) There have been a great number of attempts to find a novel PPARg agonist that is structurally different from thiazolidinedione derivatives and has higher efficacy and safety. Thiazolidinedione moiety was replaced by oxadiazolidinedione and isoxazolidinedione in YM-440 and JTT-501, respectively (Fig. 1). 8,9) Endogenous ligands for PPARg have been reported to be fatty acids and eicosanoids, such as 15-deoxy-D 12,14 -prostaglandin J 2 .2,10) Thus, a number of carboxylic acid derivatives have been designed and synthesized to enhance drug-protein interaction and to modify PPAR subtype selectivity ( Fig. 1) 2, [11][12][13] ; however, no nonthiazolidinedione derivatives have been developed successfully as new anti-diabetic drugs; therefore, further efforts are necessary to identify a structurally new PPARg agonist.As shown in Fig. 1, some recent PPARg agonists are benzene derivatives with carboxylic acid moiety and two lipophilic moieties, which are postulated to have lipophilic interaction with two regions of a PPARg protein.14) However, in these compounds, a carboxylic acid moiety, lipophilic moiety and benzyl moiety with a lipophilic chain are attached to a central atom (C or N) via a single bond, thus, each moiety can bend and/or rotate freely (Fig. 1). We hypothesized that in these carboxylic acid-type derivatives, the limitation of movement of the three moieties and fixation of their direction may enhance their PPARg agonist activity and reduce their side effects. In the present study, a tyrosine derivative was cyclized to a 1,2,3,4-tetrahydroisoquinoline derivative and then various side chains were introduced into the 2nd and 7th positions of the 1,2,3,4-tetrahydroisoquinoline ring (Fig. 2). Biological activities were evaluated in a series of 1,2,3,4-tetrahydroisoquinoline derivatives and their structure-activity relationships are discussed.Chemistry The general approach to the synthesis of (S)-2-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives 19 ...

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confidence: 99%

Synthesis and Biological Evaluation of (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: A Novel Series of PPAR.GAMMA. Agonists

Azukizawa

Kasai

Takahashi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The profile of a dual PPAR-α,γ agonist appears well suited as a treatment for type 2 diabetes [79] because of the insulinsensitizing/glucose-controlling potential of PPAR-γ agonists, the molecular target of TZDs [80][81][82][83], in combination with the positive lipid-and cholesterol modulating activities of PPAR-α agonists, the molecular target of the fibrates [84]. To fulfill this dual action a new class of compounds, α-alkoxyphenylpropanoic acid derivatives, were made and tested.…”

Section: Dual Ppar-/mentioning

confidence: 99%

Non-Insulin Dependent Diabetes Mellitus: Present Therapies and New Drug Targets&#

Das¹,

Chakrabarti

2005

MRMC

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Type 2 Diabetes Mellitus (DM) or Non-Insulin Dependent Diabetes Mellitus (NIDDM) accounts for 90-95% of all diabetes cases and has become a major health concern over the years. This disease has assumed frightening proportions due to unhealthy food habits and sedentary life style. About a decade ago, due to the absence of defined molecular targets or an understanding of disease pathophysiology, treatment of this disease was mostly focused on insulin secretion or administration of external insulin. During the past decade however, advent of genomics and proteomics has helped in understanding the molecular alteration characteristics of NIDDM. Untreated type 2 diabetes leads to several complications such as hyperlipidemia, hypertension and atherosclerosis--collectively known as Syndrome X. Though United Kingdom Prospective Diabetes Study (UKPDS) showed that normalization of hyperglycemia could prevent majority of diabetes complications, the available treatment regime does not adequately normalize the blood glucose level in type 2 diabetic patients. Currently, four distinct classes of oral hypoglycemic agents are available, some of which can act as lipid lowering agents as well. The efficacy and side effect profiles of these drugs are still to be optimized, so there is an unmet need for better candidates. Several new targets as well as better drugs for old targets are under investigation across the world. Availability of such drugs, based on the validated targets, may lead to a new therapeutic paradigm for the prevention of diabetes as well as complications arising out of it. The current review will deal with existing oral therapies for type 2 diabetes as well as the emerging therapeutic targets.

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“…Furthermore, TZD derivatives have attracted very significant biochemical interest, owing to the presence of the TZD moiety in the structures of several naturally occurring molecules with important pharmacological properties such as antidiabetic, antibiotic, and antifungal activities [3–7]. In this context, the synthesis of TZD derivatives continues to attract attention and provides an interesting challenge [8–13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological activities of some new thiazolidine derivatives containing pyrazole ring system

Nishida¹,

Maruoka²,

Yoshimura³

et al. 2011

Journal of Heterocyclic Chem

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As a part of systematic investigation of synthesis and biologically active compounds of thiazolidine (TZD) derivatives containing pyrazole ring system, several new pyrazole-TZD derivatives 8aÀd and 9aÀd have been synthesized. Compounds 8aÀd were prepared from N-substituted TZDs 6aÀd and 1H-pyrazole-4carboxaldehyde 7 by Knoevenagel-type reaction. Treatment of 8aÀd with sodium hydride at room temperature caused dimerization reaction to afford the corresponding spirocompounds 9aÀd. All the synthesized compounds were characterized by spectroscopic analysis. In vitro, the synthesized compounds 8aÀd and 9aÀd were tested for their growth inhibitory activity in A549 lung cancer, B16F10 murine melanoma, and HeLa human uterine carcinoma cells and for their differentiation of 3T3-L1 preadipocytes to adipocytes. The results showed that compound 8c possessed growth inhibitory effect of B16F10 cells (IC 50 ¼ 27 lM) and compounds 9c,d had induction effect on the differentiation of 3T3-L1 preadipocytes.

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Novel thiazolidine-2,4-diones as potent euglycemic agents.

Cited by 77 publications

References 1 publication

Synthesis and Biological Evaluation of (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: A Novel Series of PPAR.GAMMA. Agonists

Synthesis and Biological Evaluation of (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: A Novel Series of PPAR.GAMMA. Agonists

Non-Insulin Dependent Diabetes Mellitus: Present Therapies and New Drug Targets&#

Synthesis and biological activities of some new thiazolidine derivatives containing pyrazole ring system

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