Inhibitory action of .alpha.-(4-chlorophenoxy)-.alpha.-methylpropionic acid analogs on cholesterol biosynthesis and lipolysis in vitro

Abstract

The antagonist activity of the title compound 2 and some open chain and cyclic analogs on glycerol release from adipose tissue and incorporation of mevalonate-#-1"^into nonsaponifiable products of rat liver homogenate in vitro is discussed. Greater structural specificity was observed for the inhibition of cholesterol biosynthesis than for inhibition of lipolysis. A proposed mechanism for the antilipolytic effect of 2 is described.

Structural requisites of 2‐(p‐chlorophenoxy)propionic acid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC‐1

“…In order to maximise the inward currents at negative voltages, we performed the inside‐out patch‐clamp measurements with a high intracellular chloride concentration, allowing a precise determination of apparent inhibition constants ( K D ). With the exception of analogues N.2 (CPA) and N.11 that were purchased from Sigma‐Aldrich (Milano‐Italy), all the tested compounds were synthesised in our laboratory according to procedures previously reported: analogues N.3 and N.4 (Bettoni et al ., 1987); analogues N.5 and N.6 (Bettoni et al ., 1992); analogue N.7 (Calleri et al ., 2002); analogues N.8–N.10 (Bettoni et al ., 1992); analogue N.12 (Massolini et al ., 1990); analogue N.13 (Romstedt et al ., 1996); analogue N.14 (Kuchar et al ., 1979); analogue N.15 (Ferorelli et al ., 1997); analogues N.16 and N.17 (Ferorelli et al ., 2001); analogues N.18 and N.19 (Loiodice et al ., 1993); analogue N.20 (Witiak et al ., 1971b); analogue N.21 (Witiak et al ., 1971a); analogues N.22–N.24 (Liantonio et al ., 2002); analogues N.25–N.30 (Carbonara et al ., 2001); analogues 31–33 were prepared according to the procedure reported for compound 27 starting from the suitable diethyl 2‐(4‐substituted phenoxy)malonates and 4‐chlorophenoxy‐ or phenoxy propyl‐bromides, respectively.…”

Enzymatic hydrolysis of esters from 2-carboxy-6-methoxy-2,3-dihydrobenzofuran acid

“…The acid 5 was prepared following the procedure shown in Figure 1, which has been described in the literature (Fuson et al, 1944;Witiak et al, 1971), starting with the umbeliferone 2. For this study, the esters (6a-g) for the enzymatic resolution were obtained through the reaction of 5 with the corresponding alcohols: methyl, ethyl, isopropyl, n-butyl, isobutyl, benzyl and heptyl, in the presence of p-toluenesulfonic acid.…”

9-Chloro-2,3-dihydro-5H-1,4-dioxepino[6,5-b]benzofuran, a novel antilipidemic agent structurally related to clofibrate

“…The organic layer was dried (Na2S04) and filtered and the solvent removed under reduced pressure. The resulting solid was recrystallized from EtOH affording 6.4 g (88%) of white crystals: mp 128-129°(lit.12 mp 126-127°); NMR (CDC13) i 1.28-1.58 (3 H, t, CH3), 4.25-4.68 (2 H, q, CH2), 7.10-7.74 [4 H, m, aromatic (3) and methine (1)].…”

“…In previous reports from our laboratory we have considered the differential biological effects of certain benzodioxane, chroman, and dihydrobenzofuran analogs of clofibrate (1) on inhibition of lipolysis and cholesterol biosynthesis in vitro,1•2 inhibition of lipoprotein lipase in vitro,3 hypolipidemic activity in a Triton WR-1339 induced hyperlipidemic rat model,4•5 and hepatic drug metabolism. 6 In all cases the ethyl esters of the various analogs were employed for biological studies in rats since we were interested in assessing new compounds synthesized relative to 1 which is administered as an ethyl ester.…”

“…HL-12740 from the National Heart and Lung Institute. 1 Abstracted in part from a dissertation by G.K.P. presented to the Graduate School of The Ohio State University, 1974. t Undergraduate research participant, summer, 1974. Chemistry.…”