Hypolipidemic substituted 1,3-benzodioxole-2-carboxylates

Jm, Grisar; Gp, Claxton; Ra, Parker; Fp, Palopoli; Kariya, Takashi

doi:10.1021/jm00253a012

Cited by 6 publications

(5 citation statements)

References 9 publications

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“…Two general precedented approaches to the targeted molecules were revealed through retrosynthetic analyses ( Figure ). The materials that contain two oxygen atoms attached directly to the α-carbon of the acetate moiety ( 7 , 8 ) should be available through condensation of the appropriate diol with a dihaloacetic acid ( , ). The remaining two materials, 6 and 9 , could conceptually be prepared through intramolecular nucleophilic ring opening of an epoxide by a phenolic hydroxyl followed by adjustment of the oxidation state of the resulting alcohol ( − ).…”

Section: Resultsmentioning

confidence: 99%

“…The overall result of this transformation was regiospecific arylation of a 1,2,4trihydroxybenzene. Cyclization to acid 7 was then effected under previously described conditions (25) and the acidic product converted to the corresponding methyl ester, 7a, for ease of purification.…”

Section: Conformationalmentioning

confidence: 99%

“…The requisite "regioselective" alkylation was then achieved by reaction of this phenol with epichlorohydrin to give disubstituted acetophenone 24. The new phenol was finally revealed, as its acetate, by Baeyer-Villiger oxidation of 24; base-catalyzed hydrolysis of the resulting epoxy acetate (25) resulted in simultaneous deesterification and cyclization to form the dioxin ring (26). Attempted oxidation of the primary alcohol of 26 under a variety of standard conditions (Jones reagent, PCC, Swern) failed to provide the desired acid product, 9, or the corresponding aldehyde.…”

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confidence: 99%

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Origin of Enantiomeric Selectivity in the Aryloxyphenoxypropionic Acid Class of Herbicidal Acetyl Coenzyme A Carboxylase (ACCase) Inhibitors

Turner¹,

Pernich²

2002

J. Agric. Food Chem.

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Molecular modeling was used to propose an "active conformation" for the R-2-phenoxypropionic acid portion of the aryloxyphenoxypropionic acid series of herbicidal acetyl CoA carboxylase (ACCase) inhibitors. This candidate active conformation is a low-energy conformer with the R-methyl distal to the phenoxy fragment, stabilized by the generalized anomeric effect around the propionate ether bond; the inactive S-enantiomer has difficulty accessing this conformation due to steric interaction of the S-methyl with the o-hydrogen of the phenyl. This candidate conformation was challenged by preparation of a series of novel rigid analogues. ACCase inhibition data suggest that the systems which contain a fused five-membered, but not a six-membered, ring present the necessary pharmacophore to the active site of ACCase, confirming the active conformation hypothesis and demonstrating that the precise placement of the carboxylate relative to the phenyl group is more critical than the placement of the methyl.

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Section: Resultsmentioning

confidence: 99%

Section: Conformationalmentioning

confidence: 99%

mentioning

confidence: 99%

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Origin of Enantiomeric Selectivity in the Aryloxyphenoxypropionic Acid Class of Herbicidal Acetyl Coenzyme A Carboxylase (ACCase) Inhibitors

Turner¹,

Pernich²

2002

J. Agric. Food Chem.

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“…Since phenyl and phenoxy analogs of clofibrate are generally good to very potent hypolipidemic agents (29)(30)(31) and insertion of phenyl groups increases lipid solubility, it seemed to us to be of interest to consider the biological results obtained with the phenyl, C1, and H analogs in terms of the calculated log P values (Table lid for the corresponding free carboxylic acids, hydrolysis products. The log P values for the carboxylic acids, rather than the esters, were determined and used for correlation purposes since Thorp (32) had proposed that the free acid is the active form of clofibrate, and we have shown that several clofibrate analogs undergo rapid hydrolysis by serum esterase preparations (33).…”

Section: Discussionmentioning

confidence: 99%

Comparative antilipidemic effects of various ethyl 5‐substituted benzofuran‐, 2,3‐dihydrobenzofuran‐, and 3(2H)‐benzofuranone‐2‐carboxylate analogs of clofibrate in a triton hyperlipidemic rat model

Witiak

Newman

Poochikian

et al. 1976

Lipids

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The antilipidemic properties of certain benzofuran-, 2,3-dihydrobenzofuran-, and 3(2H)-benzofuranone-2-carboxylate analogs of clofibrate in a hyperlipidemic rat model are described. The hyperlipidemia was induced by intraperitoneal injection of Triton WR-1339. The results were analyzed in light of structural modifications as well as the lipid solubility of substituted compounds as assessed by a consideration of calculated log P values. Comparisons are made between the activity of these compounds and the activity of related cyclic analogs previously reported. Among the various compounds tested, only the 5-C1 and phenylsybstituted dihydrobenzofurans were selective against elevated serum cholesterol levels in this animal model. The data presented support the hypothesis that the cholesterol and triglyceride lowering activity of clofibrate related analogs in this animal model may be separated through a consideration of log P, conformational, and electronic changes. The proposal is advanced that relatively minor structural modification of clofibrate related analogs may lead to compounds which are not only selective in the Triton model but also to compounds which are likely to exert their effects by differing modes of action.

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“…Anal. (CieHsoOg) C, H 6-PhenyIchroman-2-carboxylic Acid (24). A solution of chromone acid 21 (2.6 g, 0.01 mol) and preequilibrated 10% Pd/C (0.5 g) in 50 ml of AcOH was hydrogenated at 40 psi and 70 ± 5°for 2 hr.…”

Section: -Cyclohexylchroman-2-carboxylic Acid (23)mentioning

confidence: 99%

Synthesis of ethyl 6-substituted-chroman- and -chromone-2-carboxylates. Comparative structure-activity study employing the 6-phenyl and phenoxy analogs in the triton hyperlipidemic rat model

Witiak¹,

Heilman²,

Sankarappa³

et al. 1975

J. Med. Chem.

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To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.

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Hypolipidemic substituted 1,3-benzodioxole-2-carboxylates

Cited by 6 publications

References 9 publications

Origin of Enantiomeric Selectivity in the Aryloxyphenoxypropionic Acid Class of Herbicidal Acetyl Coenzyme A Carboxylase (ACCase) Inhibitors

Origin of Enantiomeric Selectivity in the Aryloxyphenoxypropionic Acid Class of Herbicidal Acetyl Coenzyme A Carboxylase (ACCase) Inhibitors

Comparative antilipidemic effects of various ethyl 5‐substituted benzofuran‐, 2,3‐dihydrobenzofuran‐, and 3(2H)‐benzofuranone‐2‐carboxylate analogs of clofibrate in a triton hyperlipidemic rat model

Synthesis of ethyl 6-substituted-chroman- and -chromone-2-carboxylates. Comparative structure-activity study employing the 6-phenyl and phenoxy analogs in the triton hyperlipidemic rat model

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