Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

Abstract

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

“…[ 55 , 56 , 57 , 58 ]. These heterocyclic nuclei possess a broad spectrum of medicinal potential such as an anti-microbial [ 59 ], antimalarial [ 60 ], anti-anxiety [ 61 ], anti-cancer [ 62 ], anti-depressant [ 63 ], anti-tubercular [ 64 ], anti-virus [ 65 ], anti-protozoal [ 66 ], and anti-convulsant, etc. Several heterocyclic analogs have been reported to affect PPAR in different diseases [ 67 , 68 , 69 , 70 , 71 , 72 ].…”

Triterpenic Acid Amides as a Promising Agent for Treatment of Metabolic Syndrome

“…Compound 13 was obtained in 85% yield, using an adapted procedure [23] through the reaction of tyrosol derivative 11 with (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl) propanoate 12 in the presence of diisopropylazodicarboxylate (DIAD) and triphenylphosphine in THF.…”

Discovery of TD-0212, an Orally Active Dual Pharmacology AT1 Antagonist and Neprilysin Inhibitor (ARNI)

“…The 5-position of the imidazole ring in the ARB losartan has been shown to accommodate a wide range of substituents, including some that provide a second pharmacological activity. − Using a similar strategy, we linked a losartan analog (Intermediate A) to the terminal carboxylic acid of thiorphan, a thiol-based inhibitor of NEP. While thiol-based drugs are associated with complex PK/PD relationships and development risks, thiorphan was preferred over other NEP inhibitors due to its low molecular weight and high potency (Scheme ).…”