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Biomedical subjects

J R Baldwin

Publications and source records attributed to J R Baldwin.

8 recordsLinked to original sources
PubMed1979

2-Indanpropionic acids: structural leads for prostaglandin F2alpha antagonist development.

A rationale is presented for the development of prostaglandin F2alpha receptor antagonists. The target analogue, 5,6-(dibenzyloxy)-1-oxo-2-propyl-2-indanpropionic acid (3), was shown to have selective activity for antagonism of PGF2alpha when compared to the antagonism of acetylcholine and KCl on the mouse ileum, whereas other 2-indanpropionic acids (1, 2, 4), not substituted with benzyl functions, were considerably less active and nonselective. The results suggest that 3 may serve as a lead compound for further drug development.

Acetylcholine↗
PubMed1979

Synthesis and pharmacological evaluation of cis-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-ones. Tricyclic analogues related to the antilipidemic drug clofibrate.

The chemistry and pharmacology of two delta-lactones, cis-6-chloro-9a-methyl-3,4,4a,9a-tetrahydro-1H-pyrano[3,4-b]benzofuran-1-one (2) and the 9a-demethyl analogue 3, are reported. Lactones were prepared from dihydrobenzofuran precursors possessing geometrical configurations confirmed both by synthesis and 1H NMR spectroscopy. All cis-dihydrobenzofurans exhibited Jvic = 9.0-10.8 Hz, whereas their trans isomers exhibited Jvic = 5.0--6.0 Hz in agreement with predictions based on the Karplus equation. The pharmacological profiles for 2 and 3 were compared to that of clofibrate (1) in normal male Sprague-Dawley rats. Using equimolar doses (0.4 mmol/kg, po, twice daily for 7 days), 1 exhibited both anticholesterolemic and antitriglyceridemic activity, lactone 2 exhibited only antitriglyceridemic activity, and 3 was inactive as an antilipidemic agent. No correlation was observed for inhibition of hepatic HMG-CoA reductase activity and serum cholesterol lowering.

Animals↗
PubMed1978

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.

The antilipidemic properties of diethyl (4balpha,4calpha,9aalpha,4balpha)-3,6-dichlorocyclobutal[1,2-b:3,4-b']bisbenzofuran-9a,9b(4bH,4cH)-dicarboxylate, herein termed dimer 8, were studied in sucrose-fed and in Triton-induced hyperlipidemic rats. Whereas clofibrate (0.4 mmol/kg) exhibited both anticholesterolemic and antitriglyceridemic activity, dimer 8 showed only antitriglyceridemic properties at the lower dose (0.2 mmol/kg) in sucrose-fed rats. Dimer 8 only lowered serum triglycerides levels in Triton WR-1339 hyperlipidemic rats, whereas clofibrate lowered both cholesterol and triglyceride levels. In the chronic sucrose-fed model, dimer 8 and clofibrate lowered hepatic HMG-CoA reducatase activity and produced significant elevations in several parameters of hepatic drug metabolism. No positive relationship between serum cholesterol lowering and reduction of hepatic HMG-CoA reductase activity was observed by these agents in sucrose-fed rats.

Animals↗
PubMed1978

Synthesis and pharmacological evaluation of a clofibrate-related tricyclic spirolactone, 5-chloro-4',5-dihydrospiro[benzofuran-2(3H),3'(2'H)-furan]-2'-one.

The chemistry and pharmacology of the title compound, spirolactone 4, are reported. The synthesis represents a new approach to the preparation of spiro compounds. The pharmacological profiles of 4 are compared to that of clofibrate in Triton-induced hyperlipidemic, sucrose-fed, and normal Sprague-Dawley rat models. Clofibrate was effective in all animal models, but the spirolactone 4 exhibited antitriglyceridemic activity only in the Triton model. The inactivity of 4 in sucrose- and chow-fed rats could not be attributed to a resistance to hydrolysis by serum esterases. Comparative studies revealed that inhibition of hepatic HMG-CoA reductase activity may not be an index of hypocholesterolemic action in sucrose-fed rats. Additionally, only clofibrate exhibited significant changes in components of the hepatic microsomal monooxygenase system.

Animals↗
PubMed1978

Pharmacology on rat ileum of certain 2-substituted 3-(dimethylamino)-5,6-dimethoxyindenes related to 5,6-(methylenedioxy)indene calcium antagonists.

Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)-10(-3) M) and exhibited neither spasmogenic nor spasmolytic activity at lower (10(-6)-10(-5) M) concentration. The results are compared to the methyl and 2-ethyl analogues. At 10(-4) M only the butyl analogue was capable of moderate antagonism of acetylcholine and at 10(-3) M all four analogues were capable of moderately antagonizing the actions of acetylcholine.

Acetylcholine↗
PubMed1976

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.

The synthesis for the title lactone 2, designed to be an antagonist of the enzyme HMG-CoA reductase (E.C.1.1.1.34), is described. Lactone 2, its synthetic tricyclic hemiacetal precursor 4, and clofibrate were investigated for their antilipidemic activity in 7-day treated normal and in Triton WR-1339 induced hyperlipidemic male Sprague-Dawley rats. After 7-day drug administration to normal rats, lactone 2 was less effective than clofibrate in lowering HMG-CoA reductase activity and serum cholesterol; however, unlike clofibrate, lactone 2 did not increase liver weight or liver-body weight ratio or lower serum triglycerides. Since hemiacetal 4 selectively influenced triglycerides in normal animals, lactone 2 and hemiacetal 4 appear to have differential hypolipidemic effects. In the Triton hyperlipidemic model 2 and 4 lowered elevated triglycerides; only 4 significantly reduced elevated cholesterol levels; but neither 2 nor 4 was as effective as clofibrate. Differences in the observed antilipidemic properties for clofibrate, 2, and 4 in the two animal models are discussed. On the basis of preliminary biological data described in this article it is concluded that tricyclic analogues 2 and 4 represent reasonable leads for the development of new antilipidemic agents.

Animals↗