- SSTR5 ANTAGONISTS
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This disclosure is directed, at least in part, to SSTR5 antagonists useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the SSTR5 antagonists are gut-restricted compounds. In some embodiments, the condition or disorder is a metabolic disorder, such as diabetes, obesity, nonalcoholic steatohepatitis (NASH), or a nutritional disorder such as short bowel syndrome.
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Paragraph 00318
(2021/06/11)
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- Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition
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We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.
- Liu, Weiguo,Shao, Pengcheng P.,Liang, Gui-Bai,Bawiec, John,He, Jiafang,Aster, Susan D.,Wu, Margaret,Chicchi, Garry,Wang, John,Tsao, Kwei-Lan,Shang, Jin,Salituro, Gino,Zhou, Yun-Ping,Li, Cai,Akiyama, Taro E.,Metzger, Daniel E.,Murphy, Beth Ann,Howard, Andrew D.,Weber, Ann E.,Duffy, Joseph L.
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supporting information
p. 1082 - 1087
(2018/10/31)
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- 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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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 t
- Hirose, Hideki,Yamasaki, Takeshi,Ogino, Masaki,Mizojiri, Ryo,Tamura-Okano, Yumiko,Yashiro, Hiroaki,Muraki, Yo,Nakano, Yoshihide,Sugama, Jun,Hata, Akito,Iwasaki, Shinji,Watanabe, Masanori,Maekawa, Tsuyoshi,Kasai, Shizuo
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p. 4175 - 4193
(2017/07/05)
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- HETEROCYCLIC COMPOUND
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A compound having an SSTR5 antagonist action and use of the compound as a medicament are provided. Specifically, a compound represented by the following formula: wherein each symbol is as defined herein, or a salt thereof, a medicament comprising the compound or a salt thereof, and use of the compound or a salt thereof as an agent for the prophylaxis or treatment of diabetes mellitus are provided.
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Paragraph 0571; 0572; 0573
(2015/04/15)
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- SPIRO AZETIDINE ISOXAZOLE DERIVATIVES AND THEIR USE AS SSTR5 ANTAGONISTS
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Provided is a compound represented by the following formula (1) or a salt thereof, which has an SSTR5 antagonistic action: wherein each symbol has the same definition as in the specification.
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Paragraph 0376
(2014/09/29)
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- NOVEL DIHYDROPYRIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS AND NEUROKININ-3 RECEPTOR ANTAGONISTS
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The present invention is directed to novel dihydropyridin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors and/or Neurokinin-3 (NK3) receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 51
(2012/02/02)
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- SUBSTITUTED BICYCLIC AMINES FOR THE TREATMENT OF DIABETES
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Described herein are substituted bicyclic amines. In particular, described herein are substituted bicyclic amines that are effective as antagonists of SSTR5 and useful for the treatment, control or prevention of disorders responsive to antagonism of SSTR5
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Page/Page column 39; 40
(2010/06/15)
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- SUBSTITUTED SPIROCYCLIC AMINES USEFUL AS ANTIDIABETIC COMPOUNDS
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Substituted spirocyclic amines of structural formula I are selective antagonists of the somatostatin subtype receptor 5 (SSTR5) and are useful for the treatment, control or prevention of disorders responsive to antagonism of SSTR5, such as Type 2 diabetes, insulin resistance, lipid disorders, obesity, atherosclerosis, metabolic syndrome, depression, and anxiety.
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Page/Page column 43-44
(2010/11/18)
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- Synthesis and QSAR of substituted 3-hydroxyanthranilic acid derivatives as inhibitors of 3-hydroxyanthranilic acid dioxygenase (3-HAO)
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Novel 4,5-, 4,6-disubstituted and 4,5,6-trisubstituted 3- hydroxyanthranilic acid derivatives were synthesized and their ability to reduce the production of the excitotoxin quinolinic acid (QUIN) by inhibition of brain 3-hydroxyanthranilic acid dioxygenase (3-HAO) was subsequently investigated. The potency of the compounds to inhibit 3-HAO was assayed in rat brain homogenate, while chemical stability of certain compounds was studied by HPLC. The data were used to generate quantitative structure- activity relationship (QSAR) models for potency of 3-HAO inhibition and compound stability. Compounds with longer half-lives were obtained when the difference between the HOMO and LUMO was increased, while electron withdrawing groups in the 4- and 5-positions increased the potency of 3-HAO inhibition. Selected compounds that showed high potency in vitro were also found to be efficacious inhibitors in vivo after cerebral administration in rats.
- Linderberg, Mats,Hellberg, Sven,Bjoerk, Susanna,Gotthammar, Birgitta,Hoegberg, Thomas,Persson, Kerstin,Schwarcz, Robert,Luthman, Johan,Johansson, Rolf
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p. 729 - 744
(2007/10/03)
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- 3-Hydroxy anthranilic acid derivatives for inhibiting 3-hydroxy anthranilate oxygenase
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The present invention relates to novel derivatives of 3-hydroxyanthranilic acid of the general formula I, methods for their preparation, novel pharmaceutical compositions and the use thereof for inhibiting the enzyme 3-hydroxyanthranilate oxygenase, 3-HAO
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