Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity

Abstract

Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20 c and 21 a. Compound 20 c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21 a, less potent as a dual PPARα/γ activator than 20 c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.

Synthesis and antiproliferative evaluation of novel hydroxypropyl-ferrociphenol derivatives, resulting from the modification of hydroxyl groups

“…As part of this examination, we first chose to examine the influence of its alkyl chain, for example, by replacing the terminal hydroxyl substituent with its classical bioisosteres including chloro-and thiol-to test their influence on cytotoxic activity ( Figure 2). Hydroxamate-based analogues [28] or oxime ether fragments [29][30][31] are widely applied in medicinal chemistry as ubiquitous pharmacophores that display a broad range of biological activity. By combining our hydroxypropyl-ferrociphenol skeleton with some N-substituted hydroxylamine derivatives, we were also able to probe how such substituents influence the lipophilicity and cytotoxicity of these types of molecules.…”

Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists

“…We previously described the synthesis of the key a-alkoxy propionic acid ester racemates 17a,b 33 and the resolution of the optically pure enantiomers 21a and 22a 15 . Herein, we also performed synthesis of the optically pure trifluoroethoxy derivatives 21 b and 22 b by chromatographic separation of diastereoisomeric amides 19 b and 20 b resulting of the reaction of the acid 18 b with chiral (S)-2-phenylglycinol (Scheme 2).…”

“…The organic layers were dried over MgSO 4 , filtered and evaporated under reduced pressure. The residue was purified via flash column chromatography (cyclohexane/ EtOAc 6:4), yielding 10 as a yellow solid (1.35 g, 82%); C 15…”

“…The solution was extracted twice with DCM, the organic layers were washed with a saturated aqueous sodium chloride solution, dried over MgSO 4 , filtered and evaporated under reduced pressure yielding 11 as a yellow solid (0.504 g, 92%) which can be used without further purification. C 15…”

“…As a part of our programme, we were interested in developing new SPPARcM ligands with full PPARc agonist activities as well as moderating the adverse side effects as fluid retention or bodyweight gain. We have previously described a large series of a-ethoxyphenylpropionic acids bearing a benzoyl-indole core and found that many of them were full dual PPARa/c agonists with higher selectivity for the PPARc receptor 15 . Oxime ether introduction and enantiomeric resolution within this series of compounds allowed adjustment of the PPARa/c potency ratio leading to best equally balanced PPARa/c ligands.…”