Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonists

Aoki, Tomiyoshi; Asaki, Tetsuo; Hamamoto, Taisuke; Sugiyama, Yukiteru; Ohmachi, Shinji; Kuwabara, Kenji; Murakami, Kohji; Todo, Makoto

doi:10.1016/j.bmcl.2008.01.086

Cited by 9 publications

(5 citation statements)

References 22 publications

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“…The optically active acids (R)-and (S)-12l and 12o had enantiomeric excesses (ee) greater than 98% determined by using an HPLC device (Waters Association, Milford, MA) equipped with a Chiralpack AD or AI chiral column (25 cm Â 4.6 mm) (Daicel Chemical Industries Ltd., Japan) connected to an UV detector (254 nm): mobile phase, n-Hex/EtOH = 95/5 þ 0.05% TFA; flow rate, 1.0 mL/min. Compounds 8,9a,b,11a,b, and 12a,b have been previously described. 14,15 General Procedure for the Preparation of Esters 11c-k and rac-11l-u.…”

Section: Methodsmentioning

confidence: 99%

“…Recent advances in nuclear receptor ligand discovery have led to the identification of a second generation PPARα agonists with affinities for activation in the nanomolar range compared to the micromolar range for the fibrates. Examples are the ureido-based fibric acid GW7647 ( 1 ), the phenylpropanoic acid derivative KCL1998001079 ( 2 ), the fibrate LY518674 ( 3 ), the 2,3-dihydrobenzofuran-2-carboxylic acids 4 , which are constrained analogues of fibric acid, the indaneureidothioisobutyric acids 5 , and the 1,3-dioxane-2-carboxylic acids 6 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

et al. 2009

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A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

et al. 2009

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“…These agents act by stimulating the peroxisome proliferator activated receptor-α (PPAR-α), but their agonist activity is weak and nonselective over other nuclear receptors . In an effort to identify compounds with improved potency and selectivity, the conformational constraint of the oxyacetic acid terminus of the lead compound 207 was explored by the formation of the cyclic ketal 208 , readily available synthetically by condensing the diol with methyl pyruvate . In this process, the cis- isomer was either the exclusive product or the major isomer.…”

Section: Introductionmentioning

confidence: 99%

“…The ester moiety of these dioxanes is known to preferentially adopt an axial orientation stabilized, in part, by a general anomeric effect (GAE) between the lone pairs of electrons on the ring oxygen atoms and the σ* orbital of the C–CO 2 Me bond . The dioxane 208 was 100-fold more potent than 206 and exhibited greater selectivity over the related PPAR-δ receptor . Methyl substitution of the phenyl ring enhanced both PPAR-α potency and selectivity over PPAR-δ with NS-220 ( 209 ), eliciting robust hypolipidemic activity in diabetic mice following oral administration .…”

Section: Introductionmentioning

confidence: 99%

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

Meanwell

2021

J. Med. Chem.

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Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.

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“…By modification of the substitution pattern, numerous carboxylic or phenylpropanoic acid derivatives were synthesized. Although most of them were with minimal or moderate glucose-lowering activity, they were generally well tolerated in many diabetic animal models with little side effects like body weight change, hepatotoxicity, nephrotoxicity [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Pyrimidinyl-arylpropionic acid derivatives: viable resources in the development of new antineoplastic agents

Xiong

Wang

et al. 2009

Invest New Drugs

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Numerous studies have documented that various naturally derived ligands or synthetic non-thiazolidinediones (TZD) as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown moderate or potent antitumor activities, which is PPARgamma independent or partially dependent. However, the PPARgamma agonistic or glucose-lowering activity is ranked first more often than antitumor activity to determine promising novel PPARgamma agonists for potential clinical use. In this study, we hypothesized that there might exist some compounds with less PPARgamma agonistic activity but potent antitumor activity. Thereafter, we evaluated the PPARgamma agonistic and antitumor activity of a novel series of alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives synthesized with the initial aim of developing novel PPARgamma agonists as hypoglycemic agents. MTT assay results revealed that several compounds were able to inhibit cell proliferation in a dose-dependent manner with IC(50) 12.7-29.7 microM, better than that of rosiglitazone (45.9-141 microM), although the PPARgamma agonistic activity of most compounds is much lower than rosiglitazone. Some compounds induced cell cycle arrest and apoptosis tested by Flow Cytometry. Oral administration of DH9 (100 mg/kg/d) for 21 days to BALB/c nude mice bearing xenografts including MGC-803, NCI-H460, HT-29 and OS-RC-2 cells significantly retarded tumor growth. DG8 and DJ5 showed benefits in some of the above four xenografts. Our findings demonstrate that these compounds have potent antitumor activity in vitro and in vivo and pyrimidinyl-arylpropionic acid derivatives might be viable resources in the development of new antineoplastic agents.

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Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonists

Cited by 9 publications

References 22 publications

Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

Pyrimidinyl-arylpropionic acid derivatives: viable resources in the development of new antineoplastic agents

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