Masanori Kuroha

Publications (4)10.23 Total impact

• Article: Synthesis and biological evaluation of novel (-)-Cercosporamide derivatives as potent selective PPARγ modulators.

  Akihiro Furukawa, Tsuyoshi Arita, Takehiro Fukuzaki, Makoto Mori, Takeshi Honda, Susumu Satoh, Yumi Matsui, Kenji Wakabayashi, Shinko Hayashi, Kouichi Nakamura, Kazushi Araki, Masanori Kuroha, Jun Tanaka, Satoko Wakimoto, Osamu Suzuki, Jun Ohsumi
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  ABSTRACT: Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg.
  European journal of medicinal chemistry 06/2012; 54:522-33. · 3.27 Impact Factor
• Article: Pharmacology and in vitro profiling of a novel peroxisome proliferator-activated receptor γ ligand, Cerco-A.

  Kenji Wakabayashi, Shinko Hayashi, Yumi Matsui, Takuo Matsumoto, Akihiro Furukawa, Masanori Kuroha, Naomi Tanaka, Tomoko Inaba, Shoichi Kanda, Jun Tanaka, Ryo Okuyama, Satoko Wakimoto, Tsuneaki Ogata, Kazushi Araki, Jun Ohsumi
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  ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.
  Biological & Pharmaceutical Bulletin 01/2011; 34(7):1094-104. · 1.66 Impact Factor
• Article: Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives.

  Akihiro Furukawa, Tsuyoshi Arita, Susumu Satoh, Kenji Wakabayashi, Shinko Hayashi, Yumi Matsui, Kazushi Araki, Masanori Kuroha, Jun Ohsumi
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  ABSTRACT: In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.
  Bioorganic & medicinal chemistry letters 02/2010; 20(7):2095-8. · 2.65 Impact Factor
• Article: (-)-Cercosporamide derivatives as novel antihyperglycemic agents.

  Akihiro Furukawa, Tsuyoshi Arita, Susumu Satoh, Kazushi Araki, Masanori Kuroha, Jun Ohsumi
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  ABSTRACT: In our exploratory campaign for an antihyperglycemic agent with a novel mechanism of action, (-)-Cercosporamide 1, which is known as an antifungal agent, showed a potent plasma glucose lowering effect in hyperglycemic KK/Ta mice. The trouble was that it was accompanied by a decrease in food intake and a loss of body weight. We synthesized some (-)-Cercosporamide derivatives and succeeded to separate these actions. N,O-ketal type derivatives, especially compound 10, had the most potent plasma glucose lowering effect without affecting the food consumption or body weight.
  Bioorganic & medicinal chemistry letters 01/2009; 19(3):724-6. · 2.65 Impact Factor