ChemInform Abstract: (3‐Substituted Benzyl)thiazolidine‐2,4‐diones as Structurally New Antihyperglycemic Agents.

Nomura, Masahiro; Kinoshita, Susumu; Satoh, H; Maeda, Toshio; Murakami, Koji; Tsunoda, Masaki; Miyachi, Hiroyuki; Awano, Katsuya

doi:10.1002/chin.199926128

Cited by 1 publication

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“…Pharmacomodulations leading to KRP-297. Starting from compound (1), Nomura et al [33] have modified the length of the tensors between the cycles and the substitution on the aromatic cycles, leading to an optimal activity with KRP-297 (compound (9)). …”

Section: Modulations Of the Linkermentioning

confidence: 99%

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Structural Insight into PPARγ Ligands Binding

Farce¹,

Renault²,

Chavatte

2009

CMC

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Peroxisome Proliferator Activated Receptors (PPARs) are a family of three related nuclear receptors first cloned in 1990. Their involvement in glucidic and lipidic homeostasis quickly made them an attractive target for the treatment of metabolic syndrome, the most prevalent mortality factor in developed countries. They therefore attracted much synthetic efforts, more particularly PPARgamma. Supported by a large number of crystallographic studies, data derived from these compounds lead to a fairly clear view of the agonist binding mode into the Ligand Binding Domain (LBD). Nearly all the compounds conform to a three-module structure, with a binder group involved in a series of hydrogen bonds in front of the ligand-dependent Activation Function (AF2), a linker mostly arranged around a phenoxyethyl and an effector end occupying the large cavity of the binding site. Following the marketing of the glitazones and the observation of the hepatotoxicity of troglitazone, variations in the binder led to the glitazars, and then pharmacomodulations have been undertaken on the two other modules, leading to a large family of highly related chemical structures. Some compounds, while still adhering to the three-module structure, diverge from the mainstream, such as the phthalates. Curiously, these plasticizers were known to elicit biological effects that led to the discovery of PPARs but were not actively studied as PPARs agonists. As the biological effects of PPARs became clearer, new compounds were also found to exert at least a part of their actions by the activation of PPARgamma.

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Section: Modulations Of the Linkermentioning

confidence: 99%

“…Nomura et al [33] have modified the linker module of classical glitazones in a SAR study around a previous hit Fig. (6).…”

Section: Modulations Of the Linkermentioning

confidence: 99%