- Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARα/γ agonists
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The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
- Zhang, Hao,Ding, Charles Z.,Lai, Zhi,Chen, Sean S.,Devasthale, Pratik,Herpin, Tim,Morton, George,Qu, Fucheng,Ryono, Denis,Smirk, Rebecca,Wang, Wei,Wu, Shung,Ye, Xiang-Xang,Li, Yi-Xin,Apedo, Atsu,Farrelly, Dennis,Wang, Tao,Gu, Liqun,Morgan, Nathan,Flynn, Neil,Chu, Cuixia,Kunselman, Lori,Lippy, Jonathan,Locke, Kenneth,O'Malley, Kevin,Harrity, Thomas,Cap, Michael,Zhang, Lisa,Hosagrahara, Vinayak,Kadiyala, Pathanjali,Xu, Carrie,Doweyko, Arthur M.,Zahler, Robert,Hariharan, Narayanan,Cheng, Peter T.W.
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p. 1196 - 1205
(2015/04/27)
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- HETEROCYCLIC CARBOXYLIC ACID DERIVATIVES AND PHARMACEUTICAL COMPOSITION FOR INHIBITING LIPID ACCUMULATION CONTAINING SAME
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The present invention relates to a novel heterocyclic carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same as an active ingredient for inhibiting the accumulation of lipids in the body.
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Page/Page column 23
(2008/12/04)
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- Discovery of tertiary aminoacids as dual PPARα/γ agonists-I
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A novel series of potent dual agonists of PPARα and PPARγ, the alkoxybenzylglycines, was identified and explored using a solution-phase library approach. The synthesis and structure-activity relationships of this series of dual PPARα/γ agonists are descri
- Devasthale, Pratik V.,Chen, Sean,Jeon, Yoon,Qu, Fucheng,Ryono, Denis E.,Wang, Wei,Zhang, Hao,Cheng, Lin,Farrelly, Dennis,Golla, Rajasree,Grover, Gary,Ma, Zhengping,Moore, Lisa,Seethala, Ramakrishna,Sun, Wei,Doweyko, Arthur M.,Chandrasena, Gamini,Sleph, Paul,Hariharan, Narayanan,Cheng, Peter T.W.
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p. 2312 - 2316
(2008/02/01)
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- Alpha substituted carboxylic acids
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Alpha substituted carboxylic acids of formula (I):
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- Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl- 2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [muraglitazar/BMS-298585], a novel peroxisome proliferator-activated receptor α/γ dual agonist with efficacious glucose and lipid-l
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Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR α/γ dual agonist that shows potent activity in vitro at human PPARα (EC50 = 320 nM) and PPARγ (EC50 = 110 nM). Compound 2 shows excellent efficacy for lo
- Devasthale, Pratik V.,Chen, Sean,Jeon, Yoon,Qu, Fucheng,Shao, Chunning,Wang, Wei,Zhang, Hao,Cap, Michael,Farrelly, Dennis,Golla, Rajasree,Grover, Gary,Harrity, Thomas,Ma, Zhengping,Moore, Lisa,Ren, Jimmy,Seethala, Ramakrishna,Cheng, Lin,Sleph, Paul,Sun, Wei,Tieman, Aaron,Wetterau, John R.,Doweyko, Arthur,Chandrasena, Gamini,Chang, Shu Y.,Humphreys, W. Griffith,Sasseville, Vito G.,Biller, Scott A.,Ryono, Denis E.,Selan, Fred,Hariharan, Narayanan,Cheng, Peter T. W.
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p. 2248 - 2250
(2007/10/03)
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- ALPHA SUBSTITUTED CARBOXYLIC ACID AS PPAR MODULATORS
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Alpha substituted carboxylic acids of formula (I): wherein R' and R2 are as defined in the specification and R3 is A) formula (II); B) formula (III); C) formula (IV); and D) formula (V); wherein Y, Art, Are, AP, R4, R5, R6, R7, R6, R9, R9a, R10, R", R12, R17, ring A, and p are as defined in the specification; pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR, specifically PPAR α/y related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.
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- Studies on non-thiazolidinedione antidiabetic Agents. 2. Novel oxyiminoalkanoic acid derivatives as potent glucose and lipid lowering agents
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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 a
- Imoto, Hiroshi,Sugiyama, Yasuo,Kimura, Hiroyuki,Momose, Yu
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p. 138 - 151
(2007/10/03)
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- Antihyperglycemic activity of new 1,2,4-oxadiazolidine-3,5-diones
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A series of 1,2,4-oxadiazolidine-3,5-diones was synthesized and evaluated as oral antihyperglycemic agents in the obese insulin resistant db/db and ob/ob mouse - the two models for Type 2 diabetes mellitus. The majority of the prepared methoxy- and ethoxy-linked oxazole 1,2,4-oxadiazolidine-3,5-diones normalized plasma glucose levels at the 100 mg kg-1 oral dose in the db/db diabetic mouse model, and several amongst them reduced the glucose levels at the 20 mg kg-1 oral dose. The most potent compounds in the db/db mouse model were also active in the ob/ob mouse model normalizing the plasma glucose levels at the 20 mg kg-1 oral dose. The trifluoromethoxy analog 32 was the most active compound of the series, reducing significantly the plasma glucose levels at the 5 mg kg-1 oral dose. Oxadiazole-tailed 1,2,4-oxadiazolidine-3,5-diones were also active in both the db/db and ob/ob diabetic mouse models normalizing plasma glucose levels at the 100 mg kg-1 oral dose.
- Malamas, Michael S,Sredy, Janet,McCaleb, Michael,Gunawan, Iwan,Mihan, Brenda,Sullivan, Donald
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- Oxazolidinedione hypoglycemic agents
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Compounds of the formulae STR1 where R is cycloalkyl or aryl; R1 is alkyl, X is O or C=O; A is O or S; and B is N or CH are useful as hypoglycemic agents.
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- Azole phenoxy hydroxyureas as selective and orally active inhibitors of 5- lipoxygenase
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Azole phenoxy hydroxyureas are a new class of 5-lipoxygenase (5-LO) inhibitors. Structure-activity relationship studies have demonstrated that electronegative substituents on the 2-phenyl portion of the oxazole tail increased the ex vivo potency of these
- Malamas,Carlson,Grimes,Howell,Glaser,Gunawan,Nelson,Kanzelberger,Shah,Hartman
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p. 237 - 245
(2007/10/03)
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- ARYL-N-HYDROXYUREAS AS INHIBITORS OF 5-LIPOXYGENASE AND ANTO-ARTERIOSCLEROTIC AGENTS
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This invention relates to compounds which inhibit lipoxygenase in the metabolism of arachidonic acid and thus inhibits formation of leukotrienes which are implicated in inflammatory processes and bronchoconstriction and inhibits the oxidation of LDL which
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- Hypoglycemic hydroxyurea derivatives
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There are disclosed preparative processes and hypoglycemic compounds of the formula STR1 wherein R is hydrogen or C1 to C3 alkyl; R1 and R2 are taken together and are carbonyl; or R1 and R2 are taken separately, wherein R1 is hydrogen or R4 and R2 is--COR5 and COOR5 ; R3, R4 and R5 are each independently C1 to C9 alkyl, C3 to C7 cycloalkyl, phenyl, naphthyl, furyl, benzofuryl or thienyl or one of said groups mono- or disubstituted with C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 alkoxy-carbonyl, trifluoromethyl, fluoro or chloro; and n is 0 or 1; or pharmaceutically acceptable cationic salts thereof.
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- Studies on antidiabetic agents. 11. Novel thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic agents
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In the course of further chemical modification of the novel antidiabetic pioglitazone (AD-4833, U-72, 107), a series of 5-[4-(2- or 4- azolylalkoxy)benzyl- or -benzylidene]-2,4-thiazolidinediones was prepared and evaluated for hypoglycemic and hypolipidemic activities in insulin-resistant, genetically obese, and diabetic KKA(y) mice. Replacement of the 2-pyridyl moiety of pioglitazone by a 2- or 4-oxazolyl or a 2- or 4-thiazolyl moiety greatly enhanced in vivo potency. The corresponding 5-benzylidene-type compounds, in which a methine was used as a linker between the benzene ring and the thiazolidinedione ring, also had potent biological activity. Among the compounds synthesized, 5-[4-[2-(5-methyl-2-phenyl-4- oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione (18) exhibited the most potent activity, more than 100 times that of pioglitazone. The synthesis and structure-activity relationships for this novel series of derivatives are detailed.
- Sohda,Mizuno,Momose,Ikeda,Fujita,Meguro
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p. 2617 - 2626
(2007/10/02)
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- Thiazolidinedione derivatives, their production and use
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Thiazolidinedione derivatives of the general formula: STR1 [wherein R1 is hydrogen or a hydrocarbon residue or heterocyclic residue which may each be substituted; R2 is hydrogen or lower alkyl which may be substituted by hydroxyl group; X is an oxygen or sulfur atom; Z is a hydroxylated methylene or carbonyl; m is 0 or 1; n is an integer of 1 to 3; L and M represent independently a hydrogen atom or L and M combine with each other to cooperate jointly to form a linkage] and their salts, which are novel compounds, possess blood-glucose and blood-lipid lowering actions in mammals, and are of value as a therapeutic agent for diabetes and therapeutic agent for hyperlipemia.
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