Synthesis and Evaluation of PPARδ Agonists That Promote Osteogenesis in a Human Mesenchymal Stem Cell Culture and in a Mouse Model of Human Osteoporosis

Abstract

We synthesized a directed library of compounds to explore the structure−activity relationships of peroxisome proliferator-activated receptor δ (PPARδ) activation relative to mesenchymal stem cell (MSC) osteogenesis. Our scaffold used para-substituted cinnamic acids as a polar headgroup, a heteroatom and heterocycle core connecting units, and substituted phenyl groups for the lipophilic tail. Compounds were screened for their ability to increase osteogenesis in MSCs, and the most promising were examined for subunit specificity using a quantitative PPAR transactivation assay. Six compounds were selected for in vivo studies in an ovariectomized mouse model of human postmenopausal osteoporosis. Four compounds improved bone density in vivo, with two (12d and 31a) having activity comparable to that of GW0742, a wellstudied PPARδ-selective agonist. 31a (2-methyl-4-[N-methyl-N-[5methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamic acid) had the highest selectivity for PPARδ compared to other subtypes, its selectivity far exceeding that of GW0742. Our results confirm that PPARδ is a new drug target for possible treatment of osteoporosis via in situ manipulation of MSCs.

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

“…Compounds 14–48 were evaluated for their ability to activate PPARs using a GAL4/PPAR chimera system. In these assays, the well-established agonists GW7647 (PPARα), GW501516 (PPARδ), and rosiglitazone (PPARγ) were employed as positive controls, and we found that their EC 50 values were similar to the previously reported ones. − Their maximal responses were observed at 10 nM, 10 nM, and 1 μM, respectively. Thus, referring to the previous reports, PPAR activation by the tested compounds was normalized to the activity of GW7647 at 10 nM (PPARα), GW501516 at 10 nM (PPARδ), and rosiglitazone at 1 μM (PPARγ) to obtain relative activation potency .…”

Organophosphorus-Catalyzed Direct Dehydroxylative Thioetherification of Alcohols with Hypervalent Organosulfur Compounds

“…20 In 2021, Erhardt and co-workers reported that optimized compound 12, as a PPAR agonist, exhibited promising potential in treating osteoporosis in mammals. 21 Considering the high chemoselectivity of our new method, this enables us to take a protecting-group-free strategy to synthesize 12 from 13 instead of 16, the starting material of the previous route. Guided by this strategy, we attempted a novel route for the preparation of 12.…”

“…As the key intermediate, compound 15 was prepared according to a described process. 21 Subsequently, commercially available trans-cinnamic acid 13, which was more stable, less toxic, and cheaper than 16, underwent chlorosulfonation, followed by dehydroxylative thioetherification, giving desired product 12 (2 steps in 23% yield from 13). Compared with the previous method (8 steps, 0.4% yield from 16), this new synthesis route not only has a significantly shorter route (2 steps vs 8 steps) and higher yield (23% vs 0.4%) but also avoids harsh condition or high toxic agents such as t BuLi and MsCl, making the operation more convenient.…”

A selective and mild electrochemical defluorinative carboxylation for late-stage C(sp3)–F bond functionalization

“…Critically, in all cases the α,α-difluorocarboxylic acids were formed selectively over their monofluoro counterparts (up to 100% selectivity). We successfully performed e-DFC on arenes bearing electrondonating groups (EDG) including an N-aryl amide ( 19), an O-aryl acetate (21), and methoxy groups (16,20). Pleasingly, several benzonitriles (10,17,22,31) bearing different substitution patterns proceeded in good yield and selectivity.…”

“…Finally, we were able to access 42 from the key synthetic intermediate used in the synthesis of several PPARδ receptor agonists. 16 Not only do these examples highlight the ability of e-DFC to function as a tool for late-stage molecular editing by selectively taking advantage of otherwise inert C-F bonds but they also serve to further showcase this reaction's tolerance to a widerange of different functional groups (i.e., sulfone, thiazole, hydroxyl, thiocarbonyl, etc.) commonly seen in drug design.…”