21 results on '"Shizuo Kasai"'
Search Results
2. Discovery of phenylpyrrolidine derivatives as a novel class of retinol binding protein 4 (RBP4) reducers
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Shinji, Nakamura, Masahiro, Kamaura, Yuichiro, Akao, Natsuko, Nakamura, Atsushi, Mizukami, Akihiko, Goto, Naoki, Furuyama, Nobuo, Cho, and Shizuo, Kasai
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Structure-Activity Relationship ,Pyrrolidines ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Humans ,Pharmaceutical Science ,Molecular Medicine ,Retinol-Binding Proteins, Plasma ,Molecular Biology ,Biochemistry - Abstract
Retinol-binding protein 4 (RBP4) is a potential drug target for metabolic and ophthalmologic diseases. A high-throughput screening of our compound library has identified a small-molecule RBP4 reducer 7a, as a hit compound. Aiming to provide a suitable tool for investigating the pharmacological effects of RBP4 reducers, we conducted a structure-activity relationship study of 7a. Exploration of the aryl head, oxazole core, and propanoic acid tail of 7a resulted in the discovery of novel, potent, and orally available phenylpyrrolidine derivatives 43b and 43c. Compound 43b had a potent and long-lasting blood RBP4-level-reducing effect when orally administered to mice at a dose as low as 0.3 mg/kg.
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- 2022
3. Discovery of novel somatostatin receptor subtype 5 (SSTR5) antagonists: Pharmacological studies and design to improve pharmacokinetic profiles and human Ether-a-go-go-related gene (hERG) inhibition
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Yoshihide Nakano, Tsuyoshi Maekawa, Takashi Nakahata, Masanori Watanabe, Shinji Iwasaki, Sachie Morimoto, Asato Kina, Shizuo Kasai, Nobuyuki Takakura, Takeshi Yamasaki, Yuji Shimizu, Yumiko Okano Tamura, Tohru Yamashita, Tomoyuki Odani, Jun Sugama, and Hideki Hirose
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0301 basic medicine ,medicine.medical_specialty ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Peptide hormone ,Pharmacology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Hypoglycemic Agents ,Receptors, Somatostatin ,Receptor ,Molecular Biology ,Glucose tolerance test ,biology ,medicine.diagnostic_test ,Chemistry ,Somatostatin receptor ,Organic Chemistry ,Glucose Tolerance Test ,Ether-A-Go-Go Potassium Channels ,030104 developmental biology ,Endocrinology ,Somatostatin ,Gene Expression Regulation ,Drug Design ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Hormone - Abstract
Somatostatin (SST) is a peptide hormone comprising 14 or 28 amino acids that inhibits endocrine and exocrine secretion via five distinct G-protein-coupled receptors (SSTR1-5). SSTR5 has an important role in inhibiting the secretion of pancreatic and gastrointestinal hormones (e.g., insulin, GLP-1, PYY) through the binding of SSTs; hence, SSTR5 antagonists are expected to be novel anti-diabetic drugs. In the course of our lead generation program of SSTR5 antagonists, we have discovered a novel spiroazetidine derivative 3a. However, pharmacological evaluation of 3a revealed that it had to be administered at a high dose (100mg/kg) to show a persistent glucose-lowering effect in an oral glucose tolerance test (OGTT). We therefore initiated an optimization study based on 3a aimed at improving the antagonistic activity and mean residence time (MRT), resulting in the identification of 2-cyclopropyl-5-methoxybiphenyl derivative 3k. However, 3k did not show a sufficient persistent glucose-lowering effect in an OGTT; moreover, hERG inhibition was observed. Hence, further optimization study of the biphenyl moiety of compound 3k, focused on improving the pharmacokinetic (PK) profile and hERG inhibition, was conducted. Consequently, the introduction of a chlorine atom at the 6-position on the biphenyl moiety addressed a putative metabolic soft spot and increased the dihedral angle of the biphenyl moiety, leading to the discovery of 3p with an improved PK profile and hERG inhibition. Furthermore, 3p successfully exhibited a persistent glucose-lowering effect in an OGTT at a dose of 3mg/kg.
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- 2017
4. A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced–Obese Rats With Circadian Rhythm Change
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Shoki Okuda, Yasuyoshi Arikawa, Tomohiro Okawa, Junichi Sakamoto, Nobuyuki Amano, Shinobu Sasaki, Masanori Nakakariya, Yugo Habata, Shizuo Kasai, Natsu Hotta, Kenichi Hamagami, Masaaki Funata, Yasutaka Nagisa, Minoru Maruyama, Toshimi Nagi, and Yasunori Nio
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Male ,0301 basic medicine ,Agonist ,Hypothalamo-Hypophyseal System ,endocrine system ,Sympathetic nervous system ,medicine.medical_specialty ,medicine.drug_class ,Pituitary-Adrenal System ,Diet, High-Fat ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Weight Loss ,medicine ,Animals ,Obesity ,Circadian rhythm ,business.industry ,Suprachiasmatic nucleus ,Body Weight ,Lipid Metabolism ,Rats, Inbred F344 ,Circadian Rhythm ,Rats ,Receptors, Bombesin ,030104 developmental biology ,medicine.anatomical_structure ,Hypothalamus ,Anorectic ,Bombesin Receptor Subtype-3 ,Anti-Obesity Agents ,Corticosterone ,Energy Metabolism ,business ,Diet-induced obese ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
Bombesin receptor subtype 3 (BRS-3) is an orphan G protein-coupled receptor. Based on the obese phenotype of male BRS-3-deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced-obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic-pituitary-adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.
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- 2017
5. Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition
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Uttam Khamrai, Jumpei Aida, Mrinalkanti Kundu, Tsuneo Yasuma, Mikio Shirasaki, Shoki Okuda, Shizuo Kasai, Syunsuke Yamamoto, Asato Kina, Masashi Takahashi, Toshihiro Noguchi, Yasutaka Nagisa, Yayoi Kawata, Hideyuki Igawa, Minoru Ikoma, Yasushi Fujioka, Keiko Kakegawa, Tsuyoshi Maekawa, and Masaharu Nakayama
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Male ,0301 basic medicine ,Imidazopyridine ,Benzimidazole ,Time Factors ,Pyridones ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Thiophene ,Animals ,Cytochrome P-450 CYP3A ,Humans ,HATU ,Obesity ,Receptors, Somatostatin ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Bicyclic molecule ,Organic Chemistry ,Sulfoxide ,Rats, Inbred F344 ,Rats ,Melanin-concentrating hormone receptor ,030104 developmental biology ,chemistry ,Drug Design ,Molecular Medicine ,Benzimidazoles ,Anti-Obesity Agents ,Lead compound ,030217 neurology & neurosurgery - Abstract
Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1 H )-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2- a ]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1 H )-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1 H -benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1 . Optimization of 6a afforded a series of potent thiophene derivatives ( 6q – u ); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF 3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1 H -benzimidazol-6-yl)pyridin-2(1 H )-one ( 6s ) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats.
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- 2016
6. Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test
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Shoki Okuda, Minoru Ikoma, Masashi Takahashi, Shizuo Kasai, Yasutaka Nagisa, Hiromi Kaku, Syunsuke Yamamoto, Tsuyoshi Maekawa, Toshihiro Noguchi, Asato Kina, Keiko Kakegawa, Natsu Hotta, Yayoi Kawata, Hideyuki Igawa, Jumpei Aida, and Masaharu Nakayama
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Male ,0301 basic medicine ,Benzimidazole ,Imidazopyridine ,Indazoles ,Pyridones ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,Ames test ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,Obesity ,Receptors, Somatostatin ,Molecular Biology ,Indazole ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,Bicyclic molecule ,010405 organic chemistry ,Organic Chemistry ,Rats, Inbred F344 ,Rats ,0104 chemical sciences ,Melanin-concentrating hormone receptor ,030104 developmental biology ,chemistry ,Molecular Medicine ,Amine gas treating ,Anti-Obesity Agents - Abstract
To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50=35nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9- condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile.
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- 2016
7. Bombesin receptor subtype‐3‐expressing neurons regulate energy homeostasis through a novel neuronal pathway in the hypothalamus
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Mayumi Nishida, Natsu Hotta, Kenichi Hamagami, Masaaki Mori, Nobuyuki Amano, Masaaki Funata, Tomohiro Okawa, Shinobu Sasaki, Yasunori Nio, Junichi Sakamoto, Yasutaka Nagisa, Masanori Nakakariya, Yasuyoshi Arikawa, Minoru Maruyama, Toshimi Nagi, Shizuo Kasai, and Yugo Habata
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0301 basic medicine ,Agonist ,Male ,medicine.medical_specialty ,obesity ,medicine.drug_class ,Hypothalamus ,Nerve Tissue Proteins ,CHO Cells ,Biology ,Energy homeostasis ,Rats, Sprague-Dawley ,03 medical and health sciences ,Behavioral Neuroscience ,bombesin receptor subtype‐3 ,Eating ,Cricetulus ,Internal medicine ,medicine ,Animals ,Homeostasis ,Receptors, Somatostatin ,Dorsomedial hypothalamic nucleus ,energy homeostasis ,Original Research ,Mice, Knockout ,Neurons ,fungi ,Feeding Behavior ,Thermoregulation ,Bombesin receptor ,Rats ,Receptors, Bombesin ,030104 developmental biology ,Endocrinology ,nervous system ,neuronal pathway ,Bombesin Receptor Subtype-3 ,Energy Metabolism ,Immunostaining - Abstract
Objectives Bombesin receptor subtype‐3 (BRS‐3) has been suggested to play a potential role in energy homeostasis. However, the physiological mechanism of BRS‐3 on energy homeostasis remains unknown. Thus, we investigated the BRS‐3‐mediated neuronal pathway involved in food intake and energy expenditure. Materials and Methods Expression of BRS‐3 in the rat brain was histologically examined. The BRS‐3 neurons activated by refeeding‐induced satiety or a BRS‐3 agonist were identified by c‐Fos immunostaining. We also analyzed expression changes in feeding‐relating peptides in the brain of fasted rats administered with the BRS‐3 agonist. Results In the paraventricular hypothalamic nucleus (PVH), dorsomedial hypothalamic nucleus (DMH), and medial preoptic area (MPA), strong c‐Fos induction was observed in the BRS‐3 neurons especially in PVH after refeeding. However, the BRS‐3 neurons in the PVH did not express feeding‐regulating peptides, while the BRS‐3 agonist administration induced c‐Fos expression in the DMH and MPA, which were not refeeding‐sensitive, as well as in the PVH. The BRS‐3 agonist administration changed the Pomc and Cart mRNA level in several brain regions of fasted rats. Conclusion These results suggest that BRS‐3 neurons in the PVH are a novel functional subdivision in the PVH that regulates feeding behavior. As the MPA and DMH are reportedly involved in thermoregulation and energy metabolism, the BRS‐3 neurons in the MPA/DMH might mediate the energy expenditure control. POMC and CART may contribute to BRS‐3 neuron‐mediated energy homeostasis regulation. In summary, BRS‐3‐expressing neurons could regulate energy homeostasis through a novel neuronal pathway.
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- 2017
8. Discovery of novel 5-oxa-2,6-diazaspiro[3.4]oct-6-ene derivatives as potent, selective, and orally available somatostatin receptor subtype 5 (SSTR5) antagonists for treatment of type 2 diabetes mellitus
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Shinji Iwasaki, Shizuo Kasai, Ryo Mizojiri, Tsuyoshi Maekawa, Akito Hata, Yoshihide Nakano, Masaki Ogino, Yumiko Tamura-Okano, Masanori Watanabe, Takeshi Yamasaki, Hideki Hirose, Jun Sugama, Yo Muraki, and Hiroaki Yashiro
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0301 basic medicine ,Male ,medicine.medical_specialty ,Proton Magnetic Resonance Spectroscopy ,Clinical Biochemistry ,hERG ,Azetidine ,Pharmaceutical Science ,030209 endocrinology & metabolism ,CHO Cells ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Cricetulus ,Oral administration ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Hypoglycemic Agents ,Isonipecotic acid ,Receptors, Somatostatin ,Carbon-13 Magnetic Resonance Spectroscopy ,Molecular Biology ,IC50 ,biology ,Somatostatin receptor ,Organic Chemistry ,Type 2 Diabetes Mellitus ,Mice, Inbred C57BL ,030104 developmental biology ,Somatostatin ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,biology.protein ,Molecular Medicine - Abstract
Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity. A subsequent optimization study revealed that replacement of the 4-benzoic acid with an isonipecotic acid dramatically reduced hERG inhibition (5.6% inhibition at 30μM) by eliminating π-related interaction with hERG K+ channel, which resulted in the identification of 1-(2-((2,6-diethoxy-4'-fluorobiphenyl-4-yl)methyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)piperidin-4-carboxylic acid 25a (hSSTR5/mSSTR5 IC50=9.6/57nM). Oral administration of 25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration.
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- 2017
9. A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban
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Hideyuki Igawa, Hiroki Takahagi, Hisato Yamamoto, Manami Kaneko, Masakuni Noda, Shuji Fujiwara, Tomoyuki Nishimoto, Yusuke Kamada, Shizuo Kasai, Toshiki Tanaka, Makoto Inui, Hiroki Sakai, and Syunsuke Yamamoto
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0301 basic medicine ,Male ,Sarcomeres ,medicine.medical_specialty ,Contraction (grammar) ,Thapsigargin ,SERCA ,Pyridones ,ATPase ,030204 cardiovascular system & hematology ,Cell Line ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,In vivo ,Internal medicine ,medicine ,Animals ,Enzyme Inhibitors ,Rats, Wistar ,Pharmacology ,biology ,Endoplasmic reticulum ,Calcium-Binding Proteins ,Hemodynamics ,Skeletal muscle ,Phospholamban ,Rats ,Enzyme Activation ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,cardiovascular system ,biology.protein ,Calcium - Abstract
The cardiac sarco/endoplasmic reticulum Ca2+-dependent ATPase 2a (SERCA2a) plays a central role in Ca2+ handling within cardiomyocytes and is negatively regulated by phospholamban (PLN), a sarcoplasmic reticulum (SR) membrane protein. The activation of SERCA2a, which has been reported to improve cardiac dysfunction in heart failure, is a potential therapeutic approach for heart failure. Therefore, we developed a novel small molecule, compound A and characterized it both in vitro and in vivo. Compound A activated the Ca2+-dependent ATPase activity of cardiac SR vesicles but not that of skeletal muscle SR vesicles that lack PLN. The surface plasmon resonance assay revealed a direct interaction between compound A and PLN, suggesting that the binding of compound A to PLN attenuates its inhibition of SERCA2a, resulting in SERCA2a activation. This was substantiated by inhibition of the compound A-mediated increase in Ca2+ levels within the SR of HL-1 cells by thapsigargin, a SERCA inhibitor. Compound A also increased the Ca2+ transients and contraction and relaxation of isolated adult rat cardiomyocytes. In isolated perfused rat hearts, the compound A enhanced systolic and diastolic functions. Further, an infusion of compound A (30mg/kg, i.v. bolus followed by 2mg/kg/min, i.v. infusion) significantly enhanced the diastolic function in anesthetized normal rats. These results indicate that compound A is a novel SERCA2a activator, which attenuates PLN inhibition and enhances the systolic and diastolic functions of the heart in vitro and in vivo. Therefore, compound A might be a novel therapeutic lead for heart failure.
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- 2017
10. Development of a Novel Carbon-11 Labeled PET Radioligand for Melanin- Concentrating Hormone Receptor 1
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Lenke Tari, Hideyuki Igawa, Akihiro Takano, Miklós Tóth, Jenny Häggkvist, Christer Halldin, Shoki Okuda, Shizuo Kasai, Vladimir Stepanov, Syunsuke Yamamoto, Yasutaka Nagisa, and Marie Svedberg
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0301 basic medicine ,Pharmacology ,Ligands ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Radioligand ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Carbon Radioisotopes ,Receptors, Somatostatin ,Benzamide ,Melanins ,Hypothalamic Hormones ,medicine.diagnostic_test ,Molecular Structure ,Drug discovery ,Antagonist ,Brain ,Melanin-concentrating hormone receptor ,Rats ,Pituitary Hormones ,030104 developmental biology ,chemistry ,Hormone receptor ,Positron emission tomography ,Drug Design ,Positron-Emission Tomography ,Benzamides ,Cyclosporine ,Quinolines ,Anti-Obesity Agents ,Lead compound - Abstract
Background and Objective: Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents and many drug discovery programs have been dedicated to identify smallmolecule antagonists of melanin-concentrating hormone receptor 1 (MCHR1). The aim of this study was to develop a positron emission tomography (PET) tracer for MCHR1 for translation of preclinical pharmacology to clinic to enhance success rate of drug discovery programs. Methods: We identified 4-(cyclopropylmethoxy)-N-[8-methyl-3-({[(1-methyl-1H-pyrrol-2-yl)methyl] amino}ethyl)quinolin-7-yl]benzamide (Compound II) from Takeda MCHR1 antagonist library by utilizing binding affinity, log D value, physicochemical parameters ideal for a central nerve system agent, and synthetic feasibility of corresponding carbon-11 labeled radioligands as selection parameters for tracer candidates. Results: In the rat PET study, [11C] Compound II showed clear uptake in the caudate/putamen with the pretreatment of cyclosporine A and its uptake was higher than that in the cerebellum where expression of MCHR1 was reported to be low. Conclusion: In summary, [11C]Compound II is a promising lead compound for developing a suitable MCHR1 PET radioligand. [11C]Compound II, in combination with cyclosporine A, could be used as a research tool to visualize and quantify MCHR1 in rodents.
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- 2016
11. A novel and selective melanin-concentrating hormone receptor 1 antagonist ameliorates obesity and hepatic steatosis in diet-induced obese rodent models
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Hideyuki Igawa, Masashi Takahashi, Minoru Ikoma, Shiro Takekawa, Ayumi Ando, Shizuo Kasai, Natsu Hotta, Masaharu Nakayama, Mayumi Nishida, Shoki Okuda, Yoshinori Satomi, Yasutaka Nagisa, Syunsuke Yamamoto, and Yayoi Kawata
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0301 basic medicine ,Male ,medicine.medical_specialty ,medicine.drug_class ,Biology ,Diet, High-Fat ,03 medical and health sciences ,Estrogen-related receptor alpha ,Gene Knockout Techniques ,Mice ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,medicine ,Animals ,Obesity ,Receptors, Pituitary Hormone ,Receptor ,Insulin-like growth factor 1 receptor ,Pharmacology ,Dose-Response Relationship, Drug ,Lipogenesis ,Fatty liver ,Body Weight ,medicine.disease ,Receptor antagonist ,Melanin-concentrating hormone receptor ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Liver ,Anti-Obesity Agents ,Steatosis ,Diet-induced obese ,hormones, hormone substitutes, and hormone antagonists - Abstract
Melanin-concentrating hormone (MCH), a cyclic neuropeptide expressed predominantly in the lateral hypothalamus, plays an important role in the control of feeding behavior and energy homeostasis. Mice lacking MCH or MCH1 receptor are resistant to diet-induced obesity (DIO) and MCH1 receptor antagonists show potent anti-obesity effects in preclinical studies, indicating that MCH1 receptor is a promising target for anti-obesity drugs. Moreover, recent studies have suggested the potential of MCH1 receptor antagonists for treatment of non-alcoholic fatty liver disease (NAFLD). In the present study, we show the anti-obesity and anti-hepatosteatosis effect of our novel MCH1 receptor antagonist, Compound A. Repeated oral administration of Compound A resulted in dose-dependent body weight reduction and had an anorectic effect in DIO mice. The body weight lowering effect of Compound A was more potent than that of pair-feeding. Compound A also reduced lipid content and the expression level of lipogenesis-, inflammation-, and fibrosis-related genes in the liver of DIO mice. Conversely, intracerebroventricular infusion of MCH caused induction of hepatic steatosis as well as increase in body weight in high-fat diet-fed wild type mice, but not MCH1 receptor knockout mice. The pair-feeding study revealed the MCH-MCH1 receptor system affects hepatic steatosis through a mechanism that is independent of body weight change. Metabolome analysis demonstrated that Compound A upregulated lipid metabolism-related molecules, such as acylcarnitines and cardiolipins, in the liver. These findings suggest that our novel MCH1 receptor antagonist, Compound A, exerts its beneficial therapeutic effect on NAFLD and obesity through a central MCH-MCH1 receptor pathway.
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- 2016
12. Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives
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Uttam Khamrai, Shizuo Kasai, Minoru Ikoma, Asato Kina, Masaharu Nakayama, Jumpei Aida, Keiko Kakegawa, Yasutaka Nagisa, Masashi Takahashi, Syunsuke Yamamoto, Hideki Hirabayashi, Tsuneo Yasuma, Hideyuki Igawa, Mrinalkanti Kundu, Yayoi Kawata, Tsuyoshi Maekawa, and Shuntaro Ashina
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0301 basic medicine ,Male ,Stereochemistry ,Pyridones ,hERG ,CHO Cells ,01 natural sciences ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cricetulus ,Amide ,Drug Discovery ,Pyridine ,Structure–activity relationship ,Animals ,Humans ,Obesity ,Receptors, Somatostatin ,Phospholipidosis ,biology ,Bicyclic molecule ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Antagonist ,Imidazoles ,Combinatorial chemistry ,Rats, Inbred F344 ,0104 chemical sciences ,Melanin-concentrating hormone receptor ,Rats ,030104 developmental biology ,biology.protein ,Molecular Medicine ,Anti-Obesity Agents - Abstract
Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a)8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.
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- 2016
13. Melanin-Concentrating Hormone Receptor 1 Antagonists. Synthesis and Structure–Activity Relationships of Novel 3-(Aminomethyl)quinolines
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Yuji Ishihara, Ryoma Hara, Kaneyoshi Kato, Asano Asami, Toshiro Yamashita, Shigekazu Sasaki, Shiro Takekawa, Hitomi Ogino, Nobuhiro Suzuki, Shuntaro Ashina, Yoshihide Nakano, Masahiro Kamaura, Tomoko Kaisho, Shizuo Kasai, Toshio Tanaka, Koki Kato, Shinichi Masada, Toshihiro Imaeda, Yasutaka Nagisa, and Makoto Kamata
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Mice, Knockout ,Quinoline ,Administration, Oral ,Biological Availability ,Rats ,Melanin-concentrating hormone receptor ,Eating ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Hormone receptor ,Benzamides ,Drug Discovery ,Quinolines ,Receptor, Serotonin, 5-HT2C ,Animals ,Humans ,Molecular Medicine ,Anti-Obesity Agents ,Receptors, Somatostatin ,Serotonin Receptor 2C ,Binding affinities - Abstract
It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC(50) = 1.9 nM; human 5-HT2c receptor, IC(50) = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC(50) = 0.54 nM), potent in vitro antagonistic activity (IC(50) = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC(50)1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.
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- 2012
14. Design, Synthesis, and Structure−Activity Relationships of Thieno[2,3-b]pyridin-4-one Derivatives as a Novel Class of Potent, Orally Active, Non-Peptide Luteinizing Hormone-Releasing Hormone Receptor Antagonists
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Satoshi Sasaki, Masataka Harada, Shuichi Furuya, Shizuo Kasai, Hirokazu Matsumoto, Yoji Hayase, Toshihiro Imaeda, Nobuo Cho, Takashi Imada, Satoshi Endo, and Nobuhiro Suzuki
- Subjects
Male ,Models, Molecular ,Pyridines ,Pyridones ,Stereochemistry ,Molecular Conformation ,Administration, Oral ,CHO Cells ,Thiophenes ,Peptide hormone ,Chemical synthesis ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Species Specificity ,Oral administration ,Cricetinae ,Drug Discovery ,Animals ,Humans ,Moiety ,Structure–activity relationship ,Receptor ,Arachidonic Acid ,Chemistry ,Antagonist ,Rats ,Macaca fascicularis ,Molecular Medicine ,Luteinizing hormone ,Receptors, LHRH - Abstract
Design, synthesis, and structure-activity relationships of thieno[2,3-b]pyridin-4-one-based non-peptide luteinizing hormone-releasing hormone (LHRH) receptor antagonists are described. Starting with the thienopyridin-4-one derivative 26d (T-98475) an optimization study was performed, which resulted in the identification of a highly potent and orally bioavailable LHRH receptor antagonist, 3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-2-[4-(1-hydroxy-1-cyclopropanecarboxamido)phenyl]-5-isobutyryl-4-oxothieno[2,3-b]pyridine (33c). Compound 33c displayed subnanomolar in vitro activities for the human receptor and its oral administration caused effective suppression of the plasma LH levels in castrated male cynomolgus monkeys. Furthermore, SAR studies revealed that a hydroxyalkylamido moiety on the 2-phenyl ring is virtually equivalent to an alkylureido moiety, at least in this series of compounds.
- Published
- 2006
15. Correction to Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives
- Author
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Hideyuki Igawa, Masashi Takahashi, Keiko Kakegawa, Asato Kina, Minoru Ikoma, Jumpei Aida, Tsuneo Yasuma, Yayoi Kawata, Shuntaro Ashina, Syunsuke Yamamoto, Mrinalkanti Kundu, Uttam Khamrai, Hideki Hirabayashi, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, and Tsuyoshi Maekawa
- Subjects
Drug Discovery ,Molecular Medicine - Published
- 2016
16. Synthesis, structure-activity relationship, and pharmacological studies of novel melanin-concentrating hormone receptor 1 antagonists 3-aminomethylquinolines: reducing human ether-a-go-go-related gene (hERG) associated liabilities
- Author
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Tomohiro Okawa, Shiro Takekawa, Kazuaki Takami, Koki Kato, Yumi N. Imai, Sunghi Ryu, Makoto Kamata, Jun Kunitomo, Masaharu Nakayama, Shinichi Masada, Nobuhiro Suzuki, Yoshihide Nakano, Toshiki Murata, Masahiro Kamaura, Yuji Ishihara, Kaoru Watanabe, Hitomi Ogino, Shizuo Kasai, Yasutaka Nagisa, Tomoko Kaisho, and Shuntarou Ashina
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,Stereochemistry ,hERG ,CHO Cells ,Pharmacology ,Molecular Dynamics Simulation ,Ligands ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Cricetinae ,Drug Discovery ,Structure–activity relationship ,Animals ,Humans ,Obesity ,Receptors, Pituitary Hormone ,Receptor ,Benzamide ,biology ,Chemistry ,Quinoline ,Antagonist ,Stereoisomerism ,Ether-A-Go-Go Potassium Channels ,Rats, Inbred F344 ,Melanin-concentrating hormone receptor ,Rats ,Docking (molecular) ,Benzamides ,biology.protein ,Quinolines ,Molecular Medicine ,Anti-Obesity Agents - Abstract
Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.
- Published
- 2012
17. Melanin-concentrating hormone receptor 1 antagonists: synthesis, structure-activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives
- Author
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Kazuyoshi Aso, Michiko Tawada, Kaoru Watanabe, Makoto Kamata, Nobuhiro Suzuki, Shiro Takekawa, Yasutaka Nagisa, Tomoko Kaisho, Hitomi Ogino, Koki Kato, Yoshihide Nakano, Masahiro Kamaura, Shizuo Kasai, and Yuji Ishihara
- Subjects
Models, Molecular ,Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,Clinical Biochemistry ,Pharmaceutical Science ,CHO Cells ,Pharmacology ,Molecular Dynamics Simulation ,Biochemistry ,Benzazepine ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Cricetinae ,Drug Discovery ,Structure–activity relationship ,Animals ,Humans ,Obesity ,Receptors, Pituitary Hormone ,Binding site ,Molecular Biology ,Chemistry ,Tetrahydroisoquinoline ,Organic Chemistry ,Antagonist ,Benzazepines ,Rats, Inbred F344 ,Melanin-concentrating hormone receptor ,Rats ,Docking (molecular) ,Hormone receptor ,Molecular Medicine ,Anti-Obesity Agents ,Protein Binding - Abstract
Melanin-concentrating hormone receptor 1 (MCHR1) antagonists have been studied as potential agents for the treatment of obesity. Initial structure–activity relationship studies of in-house hit compound 1a and subsequent optimization studies resulted in the identification of tetrahydroisoquinoline derivative 23, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-[4-(4-chlorophenyl)piperidin-1-yl]butan-1-one, as a potent hMCHR1 antagonist. A homology model of hMCHR1 suggests that these compounds interact with Asn294 and Asp123 in the binding site of hMCHR1 to enhance binding affinity. Oral administration of compound 23 dose-dependently reduced food intake in diet-induced obesity (DIO)-F344 rats.
- Published
- 2011
18. ChemInform Abstract: A New Class of Potent Nonpeptide Luteinizing Hormone-Releasing Hormone (LHRH) Antagonists: Design and Synthesis of 2-Phenylimidazo[1,2-a]pyrimidin-5-one
- Author
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Masahiko Fujino, Nobuhiro Suzuki, Yoji Hayase, Nobuo Cho, Toshihiro Imaeda, Yoshiaki Shimizu, Shizuo Kasai, Shuichi Furuya, Masataka Harada, and Satoshi Sasaki
- Subjects
medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,medicine ,General Medicine ,Luteinizing hormone ,Hormone - Published
- 2010
19. A new class of potent nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists: design and synthesis of 2-phenylimidazo[1,2-a]pyrimidin-5-ones
- Author
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Shuichi Furuya, Nobuo Cho, Shizuo Kasai, Masahiko Fujino, Satoshi Sasaki, Yoshiaki Shimizu, Toshihiro Imaeda, Masataka Harada, Nobuhiro Suzuki, and Yoji Hayase
- Subjects
endocrine system ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pyrimidinones ,Peptide hormone ,Biochemistry ,Chemical synthesis ,Binding, Competitive ,Gonadotropin-Releasing Hormone ,Structure-Activity Relationship ,Drug Discovery ,Humans ,Receptor ,Molecular Biology ,Bicyclic molecule ,Molecular Structure ,Chemistry ,Organic Chemistry ,Antagonist ,Small molecule ,Drug Design ,Molecular Medicine ,Luteinizing hormone ,Receptors, LHRH ,Hormone - Abstract
The design and synthesis of a new class of nonpeptide luteinizing hormone-releasing hormone (LHRH) receptor antagonists, the 2-phenylimidazo[1,2-a]pyrimidin-5-ones, is reported. Among compounds described in this study, we identified the potent antagonist 15b with nanomolar in vitro functional antagonism. The result might suggest that the heterocyclic 5-6-ring system possessing a pendant phenyl group attached to the five-membered ring is the important structural feature for a scaffold of small molecule LHRH antagonists.
- Published
- 2002
20. Antimicrobial catechin derivatives of Agrimonia pilosa
- Author
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Satoshi Tahara, Shizuo Kasai, Sayaka Watanabe, Junya Mizutani, and Jun Kawabata
- Subjects
biology ,Traditional medicine ,Stereochemistry ,Catechin ,Plant Science ,General Medicine ,Horticulture ,biology.organism_classification ,medicine.disease_cause ,Antimicrobial ,Biochemistry ,Agrimonia pilosa ,chemistry.chemical_compound ,chemistry ,Staphylococcus aureus ,medicine ,Phenols ,Antibacterial activity ,Molecular Biology ,Antibacterial agent - Abstract
In a chemical investigation of the roots of Agrimonia pilosa , three novel catechin derivatives have been isolated. Their structure and stereochemistry were established on the basis of chemical and spectroscopic evidence. They showed antibacterial activity against Staphylococcus aureus .
- Published
- 1992
21. Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives.
- Author
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Hideyuki Igawa, Masashi Takahashi, Keiko Kakegawa, Asato Kina, Minoru Ikoma, Jumpei Aida, Tsuneo Yasuma, Yayoi Kawata, Shuntaro Ashina, Syunsuke Yamamoto, Kundu, Mrinalkanti, Khamrai, Uttam, Hideki Hirabayashi, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, and Tsuyoshi Maekawa
- Published
- 2016
- Full Text
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