α-cycloalkyl-substituted ω-keto-dicarboxylic acids as lipid regulating agents

Influence of Various Central Moieties on the Hypolipidemic Properties of Long Hydrocarbon Chain Diols and Diacids

“…Similarly, Bisgaier et al reported that ether-containing diacids were biologically active lipid regulators in vivo. , Ether diacids of 13−15 atom chain lengths proved to be the most active compounds. Our findings showed that active compounds displayed symmetrical or unsymmetrical structures with four to five methylene groups separating the central ether or ketone functionalities and the gem -dimethyl, -methyl/aryl, or -cyclopropyl substituents. − Bisgaier et al similarly reported biological activity of symmetrical or unsymmetrical ether diacids, , the compound gemcabene having a 13-atom chain length showing activity in humans . Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for gem -tetramethyl-substituted 5,5-keto-diacids and -diols, while bis(aryl-methyl) derivatives were shown to be the least active …”

“…Effect on Lipid Variables in the Obese Female Zucker Rat. To test the lipid regulating activity of these compounds, we used the obese Zucker fatty rat, Crl:(Zuc)-faBR, as a model of diabetic dyslipidemia, as described in previous articles of the same group. − The Zucker rat has a mutation in the leptin receptor that leads to a metabolic disorder similar to human non-insulin-dependent diabetes mellitus (NIDDM) or type II diabetes and causes an age-dependent progression of hypertriglyceridemia, VLDL cholesterol (VLDL-C) elevation, HDL-C reduction, impaired insulin sensitivity, hyperphagia, and marked weight gain leading to obesity. Characteristic for this rodent model is that the non-HDL-C is mainly VLDL-C with essentially no LDL-C with markedly elevated plasma triglycerides.…”

“…In the ketone series, compound 39 showed good activity, while compound 18 displaying the double bond in a side chain showed no activity. Other ketone derivatives have been extensively discussed in earlier publications. , …”

“…In our earlier studies, − we have found a chain length of 13−15 atoms to be optimal for biological activity. In addition, we established that the introduction of an oxygen atom either as an ether ( 1 ) or as a ketone ( 2 ) inside the chain increased the effect of lowering triglycerides and HDL elevation in the Zucker animal model compared to the methylene analogues.…”

“…We have recently identified several series of functionalized long chain hydrocarbon derivatives as possessing lipid-regulating activity in an animal model of diabetic dyslipidemia (i.e., the obese female Zucker fatty rat). − The work was focused on the design of long hydrocarbon chain ether 1 and keto 2,3 diols and diacids with gem -dialkyl, − alkyl/aryl, , and cycloalkyl 3 substitution to the terminal acid or hydroxymethylene functions. The in vivo pharmacologic activity of these compounds is reflected in serum triglyceride reduction, decreases in non-HDL cholesterol (non-HDL-C), and increases in HDL cholesterol (HDL-C).…”