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  1. Article ; Online: Rapid and efficient synthesis of a novel cholinergic muscarinic M

    Miura, Shotaro / Fukuda, Koichiro / Masada, Shinichi / Usutani, Hirotsugu / Kanematsu, Makoto / Cork, David G / Kawamoto, Tetsuji

    Organic & biomolecular chemistry

    2019  Volume 17, Issue 35, Page(s) 8166–8174

    Abstract: Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic ... ...

    Abstract Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic M
    MeSH term(s) Allosteric Regulation/drug effects ; Benzaldehydes/chemical synthesis ; Benzaldehydes/chemistry ; Benzaldehydes/pharmacology ; Cholinergic Agents/chemical synthesis ; Cholinergic Agents/chemistry ; Cholinergic Agents/pharmacology ; Humans ; Molecular Structure ; Receptor, Muscarinic M1/metabolism
    Chemical Substances 2-bromobenzaldehyde ; Benzaldehydes ; CHRM1 protein, human ; Cholinergic Agents ; Receptor, Muscarinic M1
    Language English
    Publishing date 2019-08-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 2097583-1
    ISSN 1477-0539 ; 1477-0520
    ISSN (online) 1477-0539
    ISSN 1477-0520
    DOI 10.1039/c9ob01718f
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors.

    Fujimoto, Jun / Okamoto, Rei / Noguchi, Naoyoshi / Hara, Ryoma / Masada, Shinichi / Kawamoto, Tetsuji / Nagase, Hiroki / Tamura, Yumiko Okano / Imanishi, Mitsuaki / Takagahara, Shuichi / Kubo, Kazuki / Tohyama, Kimio / Iida, Koichi / Andou, Tomohiro / Miyahisa, Ikuo / Matsui, Junji / Hayashi, Ryouta / Maekawa, Tsuyoshi / Matsunaga, Nobuyuki

    Journal of medicinal chemistry

    2017  Volume 60, Issue 21, Page(s) 8963–8981

    Abstract: The discovery and optimization of Δ-5 desaturase (D5D) inhibitors are described. Investigation of the 1,3-oxazolidin-2-one scaffold was inspired by a pharmacophore model constructed from the common features of several hit compounds, resulting in the ... ...

    Abstract The discovery and optimization of Δ-5 desaturase (D5D) inhibitors are described. Investigation of the 1,3-oxazolidin-2-one scaffold was inspired by a pharmacophore model constructed from the common features of several hit compounds, resulting in the identification of 3,5-diphenyl-1,3-oxazolidin-2-one 5h as a novel lead showing potent in vitro activity. Subsequent optimization focused on the modification of two metabolic sites, which provided (4S,5S)-5i, a derivative with improved metabolic stability. Moreover, adding a substituent into the upper phenyl moiety further enhanced the intrinsic activity, which led to the discovery of 5-[(4S,5S)-5-(4fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]benzene-1,3-dicarbonitrile (4S,5S)-5n, endowed with excellent D5D binding affinity, cellular activity, and high oral bioavailability in a mouse. It exhibited robust in vivo hepatic arachidonic acid/dihomo-γ-linolenic acid ratio reduction (a target engagement marker) in an atherosclerosis mouse model. Finally, an asymmetric synthetic procedure for this compound was established.
    MeSH term(s) Administration, Oral ; Animals ; Arachidonic Acid/metabolism ; Atherosclerosis/drug therapy ; Biological Availability ; Drug Discovery/methods ; Fatty Acid Desaturases/antagonists & inhibitors ; Liver/metabolism ; Mice ; Oxazolidinones/chemical synthesis ; Oxazolidinones/metabolism ; Oxazolidinones/pharmacokinetics ; Oxazolidinones/pharmacology ; Structure-Activity Relationship
    Chemical Substances Oxazolidinones ; Arachidonic Acid (27YG812J1I) ; Fatty Acid Desaturases (EC 1.14.19.-) ; delta-5 fatty acid desaturase (EC 1.14.99.-)
    Language English
    Publishing date 2017-10-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.7b01210
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  3. Article ; Online: Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist.

    Kono, Mitsunori / Ochida, Atsuko / Oda, Tsuneo / Imada, Takashi / Banno, Yoshihiro / Taya, Naohiro / Masada, Shinichi / Kawamoto, Tetsuji / Yonemori, Kazuko / Nara, Yoshi / Fukase, Yoshiyuki / Yukawa, Tomoya / Tokuhara, Hidekazu / Skene, Robert / Sang, Bi-Ching / Hoffman, Isaac D / Snell, Gyorgy P / Uga, Keiko / Shibata, Akira /
    Igaki, Keiko / Nakamura, Yoshiki / Nakagawa, Hideyuki / Tsuchimori, Noboru / Yamasaki, Masashi / Shirai, Junya / Yamamoto, Satoshi

    Journal of medicinal chemistry

    2018  Volume 61, Issue 7, Page(s) 2973–2988

    Abstract: A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, ...

    Abstract A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log  D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.
    MeSH term(s) Animals ; Autoimmune Diseases/drug therapy ; Drug Discovery ; Drug Inverse Agonism ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Gene Expression/drug effects ; Genes, Reporter/drug effects ; Interleukin-17/genetics ; Interleukin-17/metabolism ; Interleukin-23 Subunit p19/genetics ; Interleukin-23 Subunit p19/metabolism ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Molecular Structure ; Nuclear Receptor Subfamily 1, Group F, Member 3/agonists ; Receptors, Retinoic Acid/agonists ; Structure-Activity Relationship ; Th17 Cells/immunology
    Chemical Substances Il17a protein, mouse ; Il23a protein, mouse ; Interleukin-17 ; Interleukin-23 Subunit p19 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Receptors, Retinoic Acid
    Language English
    Publishing date 2018-03-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.8b00061
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  4. Article ; Online: Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds.

    Shirai, Junya / Tomata, Yoshihide / Kono, Mitsunori / Ochida, Atsuko / Fukase, Yoshiyuki / Sato, Ayumu / Masada, Shinichi / Kawamoto, Tetsuji / Yonemori, Kazuko / Koyama, Ryoukichi / Nakagawa, Hideyuki / Nakayama, Masaharu / Uga, Keiko / Shibata, Akira / Koga, Keiko / Okui, Toshitake / Shirasaki, Mikio / Skene, Robert / Sang, BiChing /
    Hoffman, Isaac / Lane, Wes / Fujitani, Yasushi / Yamasaki, Masashi / Yamamoto, Satoshi

    Bioorganic & medicinal chemistry

    2018  Volume 26, Issue 2, Page(s) 483–500

    Abstract: A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4- ... ...

    Abstract A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.
    MeSH term(s) Administration, Oral ; Animals ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Discovery ; Glycine/administration & dosage ; Glycine/analogs & derivatives ; Glycine/chemistry ; Glycine/pharmacology ; Humans ; Jurkat Cells ; Male ; Mice ; Mice, Inbred BALB C ; Models, Animal ; Models, Molecular ; Molecular Structure ; Nuclear Receptor Subfamily 1, Group F, Member 3/agonists ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics ; Structure-Activity Relationship
    Chemical Substances Nuclear Receptor Subfamily 1, Group F, Member 3 ; phenylglycinamide ; Glycine (TE7660XO1C)
    Language English
    Publishing date 2018--15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/j.bmc.2017.12.006
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  5. Article ; Online: Melanin-concentrating hormone receptor 1 antagonists. Synthesis and structure-activity relationships of novel 3-(aminomethyl)quinolines.

    Kamata, Makoto / Yamashita, Toshiro / Imaeda, Toshihiro / Tanaka, Toshio / Masada, Shinichi / Kamaura, Masahiro / Kasai, Shizuo / Hara, Ryoma / Sasaki, Shigekazu / Takekawa, Shiro / Asami, Asano / Kaisho, Tomoko / Suzuki, Nobuhiro / Ashina, Shuntaro / Ogino, Hitomi / Nakano, Yoshihide / Nagisa, Yasutaka / Kato, Koki / Kato, Kaneyoshi /
    Ishihara, Yuji

    Journal of medicinal chemistry

    2012  Volume 55, Issue 5, Page(s) 2353–2366

    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 ... ...

    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.
    MeSH term(s) Administration, Oral ; Animals ; Anti-Obesity Agents/chemical synthesis ; Anti-Obesity Agents/pharmacokinetics ; Anti-Obesity Agents/pharmacology ; Benzamides/chemical synthesis ; Benzamides/pharmacokinetics ; Benzamides/pharmacology ; Biological Availability ; Eating/drug effects ; Humans ; Mice ; Mice, Knockout ; Quinolines/chemical synthesis ; Quinolines/pharmacokinetics ; Quinolines/pharmacology ; Rats ; Receptor, Serotonin, 5-HT2C/metabolism ; Receptors, Somatostatin/antagonists & inhibitors ; Receptors, Somatostatin/genetics ; Structure-Activity Relationship
    Chemical Substances 4'-fluoro-N-(8-methyl-3-(1-pyrrolidinylmethyl)-7-quinolinyl)(1,1'-biphenyl)-4-carboxamide ; Anti-Obesity Agents ; Benzamides ; MCHR1 protein, human ; MCHR1 protein, rat ; Mchr1 protein, mouse ; Quinolines ; Receptor, Serotonin, 5-HT2C ; Receptors, Somatostatin
    Language English
    Publishing date 2012-02-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm201596h
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  6. Article ; Online: 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.

    Kasai, Shizuo / Kamata, Makoto / Masada, Shinichi / Kunitomo, Jun / Kamaura, Masahiro / Okawa, Tomohiro / Takami, Kazuaki / Ogino, Hitomi / Nakano, Yoshihide / Ashina, Shuntarou / Watanabe, Kaoru / Kaisho, Tomoko / Imai, Yumi N / Ryu, Sunghi / Nakayama, Masaharu / Nagisa, Yasutaka / Takekawa, Shiro / Kato, Koki / Murata, Toshiki /
    Suzuki, Nobuhiro / Ishihara, Yuji

    Journal of medicinal chemistry

    2012  Volume 55, Issue 9, Page(s) 4336–4351

    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). ... ...

    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.
    MeSH term(s) Animals ; Anti-Obesity Agents/chemical synthesis ; Anti-Obesity Agents/chemistry ; Anti-Obesity Agents/pharmacology ; Benzamides/chemical synthesis ; Benzamides/chemistry ; Benzamides/pharmacology ; CHO Cells ; Cricetinae ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels/genetics ; Ether-A-Go-Go Potassium Channels/metabolism ; Humans ; Inhibitory Concentration 50 ; Ligands ; Magnetic Resonance Spectroscopy ; Molecular Dynamics Simulation ; Obesity/drug therapy ; Obesity/genetics ; Obesity/metabolism ; Quinolines/chemical synthesis ; Quinolines/chemistry ; Quinolines/pharmacology ; Rats ; Rats, Inbred F344 ; Receptors, Pituitary Hormone/antagonists & inhibitors ; Receptors, Pituitary Hormone/metabolism ; Spectrometry, Mass, Electrospray Ionization ; Stereoisomerism ; Structure-Activity Relationship
    Chemical Substances Anti-Obesity Agents ; Benzamides ; Ether-A-Go-Go Potassium Channels ; Ligands ; Quinolines ; Receptors, Pituitary Hormone ; melanin-concentrating hormone receptor
    Language English
    Publishing date 2012-05-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm300167z
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