外国特許コード F200010183
整理番号 AF35-02WO
掲載日 2020年7月28日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2019JP041563
国際公開番号 WO 2020085393
国際出願日 令和元年10月23日(2019.10.23)
国際公開日 令和2年4月30日(2020.4.30)
  • 特願2018-199523 (2018.10.23) JP
発明の名称 (英語) PPARδ ACTIVATOR
発明の概要(英語) The present invention provides a peroxisome proliferator-activated receptor δ (PPARδ) activator having a novel PPARδ agonist as an active ingredient, and an exercise tolerance improver having the PPARδ activator as an active ingredient. The present invention is: a PPARδ activator for activating PPARδ transcription activity, the PPARδ activator having a guanidine derivative or a biguanidine derivative as an active ingredient; the PPARδ activator capable of fitting into the interior of a PPARδ ligand binding pocket in a state in which guanidine groups or biguanidine groups of the guanidine derivative and the biguanidine derivative are hydrogen-bonded with amino acid residues corresponding, respectively, to His 413, His 287, Thr 253, and Tyr 437 of human PPARδ among the amino acid residues constituting the interior surface of the ligand binding pocket; and an exercise tolerance improver having any of the above PPARδ activators as an active ingredient.
従来技術、競合技術の概要(英語) BACKGROUND ART
PPAR is, one of the nuclear hormone receptor superfamily is, the ligand-induced transcriptional factor. In mammals, the PPAR α, γ, δ is a family member. PPAR α is, and the endogenous ligand free fatty acids, lipolysis various data relating to the expression of the gene for regulation, hyperlipidemia and improve the targeted agent. PPAR γ is, the long-chain fatty acids such as prostaglandin or an endogenous ligand and, to facilitate the differentiation of fat cells, insulin resistance-improving agent is the target substance of the thiazolidine. PPAR δ is, are widely expressed in various tissues, physiological activity has been demonstrated that an endogenous ligand is unknown, it is therefore considered to be orphan receptor (for example, see Non-Patent Document 1). PPAR δ is, non-dependent transcriptional activity of the ligand having the Zinc finger domains having N-terminal domain,DNA binding region, and a ligand-dependent transcription activating ability of the ligand binding domain (Ligand binding domain has: LBD) are formed. PPAR δ of the amino acid sequence of the LBD, the PPAR α LBD is 70%, and 68% PPAR γ LBD of homology (sequence identity) is that (for example, see Non-Patent Document 2).
In recent years, the PPAR δ, lipid catabolism, transporting, and storing in the control of the transcriptional regulatory factor is important has been reported (for example, see Non-Patent Document 3), development of a therapeutic agent such as metabolic abnormalities as the molecular target of attention. For example, an agonist of PPAR δ by intake, exercise induced type such as the endurance of the motion effect can be increased, and, where the agonist of PPAR δ, it is possible to improve the ability to move an agent, has been reported (for example, see Patent Document 1 and Non-Patent Document 4). Agonist of PPAR δ agonists, AMPK(5' AMP-activated protein kinase) also by used in combination, to improve the effect of the movement of the subject (for example, see Patent Document 2 and Non-Patent Document 4). Otherwise, an agonist of PPAR δ administration, serve an important role in the pathogenesis of heart muscle lipid-induced stress can be suppressed in the endoplasmic reticulum (ER) (for example, Non-Patent Document 5) or, and carbon tetrachloride to liver fibrosis induced by administration, the protective effect and anti-fibrotic liver effect can be obtained (for example, Non-Patent Document 6) has been reported.
As an agonist of PPAR δ, for example, GW501516 (CAS no.: 317318-70-0) is represented by a derivative (phenoxyacetic acid) phenoxy acetic acid. Basic skeleton of the phenoxy acetic acid derivatives, a carboxyl group (- COOH) of non-polar hydrocarbons such as long-chain hydrophobic groups bonded to the chemical structure. PPAR δ agonist and phenoxyacetic acid derivative from the result of structure analysis of the complex, the ligand binding pocket of the PPAR δ, referred to as the arm 3 of the two tunnels I,II,III(arm I,arm II,arm III) cavities Y-shaped pocket is known (for example, see Non-Patent Document 7 and 8). As an agonist of PPAR δ, GW2331 (CAS no.: 190844-95-2) as a hydrophobic group is branched backbone with agents that have been developed.
On the other hand, (Metformin) is metformin, biguanides (biguanide, biguanide) one of the drug, oral treatment of diabetes mellitus has been widely used as a drug. Metformin, AMPK can be activated, and enhancing glucose uptake in skeletal muscle, liver and the control of β can be in the fatty acid has been known (for example, Non-Patent Document 9). In addition, suppressing Glycerophosphate dehydrogenase mitochondrial liver gluconeogenesis suppressed, to lower blood sugar level have been reported (for example, Non-Patent Document 10).
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • 発明者(英語)
  • OGURA Toshihiko
  • HAKOSHIMA Toshio
  • KUBO Atsushi
参考情報 (研究プロジェクト等) CREST Creation of Fundamental Technologies for Understanding and Control of Biosystem Dynamics