Antilipidemic Activity of 4-oxo-functionalized Ethyl 6-chlorochroman-2-carboxylate Analogs and a Related Tricyclic Lactone in Three Rat Models

Overview

Journal Lipids

Specialty Biochemistry

Date 1981 Jan 1

PMID 7219078

Citations 2

Authors

R C Cavestri

J A Minatelli

J R Baldwin

W Loh

D R Feller

H A Newman

C L Sober

D T Witiak

Affiliations

Soon will be listed here.

Abstract

The synthesis of ethyl cis-6-chloro-4-hydroxychroman-2-carboxylate (IV) and 6-chloro-4-hydroxy-chroman-2-carboxylic acid lactone (V) are reported. The antilipidemic properties of these compounds in 3 rat models were compared to the activity obtained for the previously synthesized related analogs ethyl 6-chlorochroman-2-carboxylate (II), ethyl 6-chlorochromanone-2-carboxylate (III) and clofibrate (I). The biologically most interesting analog, ethyl 6-chlorochroman-2-carboyxlate (II) like clofibrate (I), was an effective antitriglyceridemic and anticholesterolemic agent in Triton WR-1339 hyperlipidemic rats, sucrose-fed hyperlipidemic rats and chow-fed normolipemic rats. Ethyl 6-chlorochromanone-2-carboxylate (III) was found to be active after 7 days of administration to sucrose-fed rats. In sucrose-fed, male Sprague-Dawley rats, the comparative effects of these analogs on various hepatic drug parameters also were carried out. Consistent with previous findings, results obtained with these compounds provide evidence showing that changes in hepatic HMG-CoA reductase activity bear no relationship to serum cholesterol lowering in the sucrose-fed model.

Citing Articles

Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: I. Chow-fed animals.

OBrien M, Patel S, Mukhopadhyay A, Newman H, Feller D, Kokrady S Lipids. 1981; 16(12):903-11.

PMID: 7329211 DOI: 10.1007/BF02534996.

Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: II. High sucrose-fed animals.

Mukhopadhyay A, Patel S, OBrien M, Kokrady S, Newman H, Witiak D Lipids. 1983; 18(1):59-67.

PMID: 6835036 DOI: 10.1007/BF02534692.

References

ABEL L, LEVY B, Brodie B, KENDALL F . A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. J Biol Chem. 1952; 195(1):357-66. View

Segal P, Roheim P, EDER H . Effect of clofibrate on lipoprotein metabolism in hyperlipidemic rats. J Clin Invest. 1972; 51(7):1632-8. PMC: 292310. DOI: 10.1172/JCI106964. View

SOLONI F . Simplified manual micromethod for determination of serum triglycerides. Clin Chem. 1971; 17(6):529-34. View

SCHURR P, Schultz J, Parkinson T . Triton-induced hyperlipidemia in rats as an animal model for screening hypolipidemic drugs. Lipids. 1972; 7(1):68-74. DOI: 10.1007/BF02531272. View

Platt D, Thorp J . Changes in the weight and composition of the liver in the rat, dog and monkey treated with ethyl chlorophenoxyisobutyrate. Biochem Pharmacol. 1966; 15(7):915-25. DOI: 10.1016/0006-2952(66)90168-7. View

Goldberg A, Mellon W, Witiak D, Feller D . Comparison of hypocholesterolemic activity for cyclic analogs of clofibrate in normolipemic rats. Atherosclerosis. 1977; 27(1):15-25. DOI: 10.1016/0021-9150(77)90019-3. View

Witiak D, Newman H, Poochikian G, Fogt S, Baldwin J, Sober C . Diethyl (4baalpha,4calpha,9aalpha,9balpha)-3,6-dichlorocyclobuta[1,2-b:3,4-b']bisbenzofuran-9a,9b(4bH,4cH)-dicarboxylate: the cis,syn photodimer of ethyl 5-chlorobenzofuran-2-carboxylate, an analogue related to the antilipidemic drug clofibrate. J Med Chem. 1978; 21(8):833-7. DOI: 10.1021/jm00206a026. View

Witiak D, Cavestri R, Newman H, Baldwin J, Sober C, Feller D . Synthesis and pharmacological evaluation of a clofibrate-related tricyclic spirolactone, 5-chloro-4',5-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2'-one. J Med Chem. 1978; 21(12):1198-202. DOI: 10.1021/jm00210a005. View

Holub W, Galli F . Automated direct method for measurement of serum cholesterol, with use of primary standards and a stable reagent. Clin Chem. 1972; 18(3):239-43. View

10.

Lewis N, Witiak D, Feller D . Influence of clofibrate (ethyl-4-chlorophenoxyisobutyrate) on hepatic drug metabolism in male rats. Proc Soc Exp Biol Med. 1974; 145(1):281-5. DOI: 10.3181/00379727-145-37793. View

11.

Witiak D, Stratford E, Nazareth R, Wagner G, Feller D . 6-Chlorochroman-2-carboxylic acids. Synthesis and biological evaluation as antagonists for cholesterol biosynthesis and lipolysis in vitro. J Med Chem. 1971; 14(8):758-66. DOI: 10.1021/jm00290a021. View

12.

Witiak D, Poochikian G, Feller D, Kenfield N, Newman H . 9-Chloro-2,3-dihydro-5H-1,4-dioxepino(6,5-b)benzofuran, a novel antilipidemic agent structurally related to clofibrate. J Med Chem. 1975; 18(10):992-6. DOI: 10.1021/jm00244a008. View

13.

Kinoshita T, Horie S . Studies on P-450. 3. On the absorption spectrum of P-450 in rabbit liver microsomes. J Biochem. 1967; 61(1):26-34. DOI: 10.1093/oxfordjournals.jbchem.a128517. View

14.

Tolman E, TEPPERMAN H, TEPPERMAN J . Effect of ethyl p-chlorophenoxyisobutyrate on rat adipose lipoprotein lipase activity. Am J Physiol. 1970; 218(5):1313-8. DOI: 10.1152/ajplegacy.1970.218.5.1313. View

15.

Witiak D, Kuwano E, Feller D, Baldwin J, Newman H, Sankrappa S . Synthesis and antilipidemic properties of cis-7-chloro-3a, 8b-dihydro-3a-methylfuro[3,4-b]benzofuran-3(1H)-one, a tricyclic clofibrate related lactone having a structural resemblance to mevalonolactone. J Med Chem. 1976; 19(10):1214-20. DOI: 10.1021/jm00232a009. View

16.

LOWRY O, ROSEBROUGH N, FARR A, RANDALL R . Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75. View

17.

Phillips A, Langdon R . Hepatic triphosphopyridine nucleotide-cytochrome c reductase: isolation, characterization, and kinetic studies. J Biol Chem. 1962; 237:2652-60. View

18.

Witiak D, Newman H, Poochikian G, Loh W, Sankarappa S . 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. Lipids. 1976; 11(5):384-91. DOI: 10.1007/BF02532845. View

19.

EGGSTEIN M . [A new determination of the neutral fats in blood serum and tissue. II. Reliability of the method, other neutral fat determinations, normal values for triglycerides and glycerin in human blood]. Klin Wochenschr. 1966; 44(5):267-73. DOI: 10.1007/BF01747717. View

20.

Lewis N, Feller D, Poochikian G, Witiak D . Differential effects of benzodioxane, chroman, and dihydrobenzofuran analogs of clofibrate on various parameters of hepatic drug metabolism. J Med Chem. 1974; 17(1):41-5. DOI: 10.1021/jm00247a009. View