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Literature References
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Taketoshi Okubo, Toshihito Kumagai, Takaaki Ishii, Toshio Nakamura, Kumi Abe, Yuri Amada, Tomoko Ishizaka, Xiang-Min Sun, Yoshinori Sekiguchi, Shigetada Sasako, Takanori Shimizu, Takayuki Nagatsuka
Aminopyrrolidine Compound
In this patent from Taisho Pharmaceutical Co. and Nissan Chemical Ltd., scientists disclose a series of aminopyrrolidine containing MC4 receptor antagonistics. Such antagonists are described as prophylactic and therapeutic agents for mood disorders such as depression, anxiety disorder, anorexia, cachexia, pain and drug dependence. Numerous examples are provided, many of which contain a cyclopropyl-phenyl moiety. The synthesis of the cyclopropyl-phenyl portion of the molecule begins from a substituted phenyl-cyclopropanecarbonitrile, such as BioBlocks CP041 and CP042. Conversion of the nitriles to the phenyl-cyclopropanecarboxylic acids, such as BioBlocks CP001 and CP002, and coupling with a variety of amino-heteroaromatic substituted pyrrolidines under standard HOBT/EDC conditions yields the final products.
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| 2. |
Hua Tu, Jay P. Powers, Jinsong Liu, Stefania Ursu, Athena Sudom, Xuelei Yan, Haoda Xu, David Meininger, Michael DeGraffenreid, Xiao He, Juan C. Jaen, Daqing Sun, Marc Labelle, Hiroshi Yamamoto, Bei Shan, Nigel P. C. Walker, Zhulun Wang
Distinctive molecular inhibition mechanisms for selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1
Scientists at Amgen report two highly potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Excess 11β-HSD1 leads to insulin resistance, therefore, inhibition of 11β-HSD1 activity may be a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. One of the two reported inhibitors contains a phenyl-cyclopropyl-triazine moeity and has a biochemical IC50 of 1.6 ± 0.5 nM.The synthesis of this inhibitor begins with 4-fluoro-phenyl-cyclopropanecarbonitrile (BioBlocks CP042). Conversion to the ester by way of the intermediate acid (BioBlocks CP002) and treatment with hydrazine provides 1-(4-fluoro-phenyl)-cyclopropanecarboxylic acid hydrazide. Condensation with N-isopropyl-4-trifluoromethoxy-thiobenzimidic acid methyl ester in refluxing pyridine affords the desired inhibitor.
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Christopher Fotsch, Michael D. Bartberger, Eric A. Bercot, Michelle Chen, Rod Cupples, Maury Emery, Jenne Fretland, Anil Guram, Clarence Hale, Nianhe Han, Dean Hickman, Randall W. Hungate, Michael Hayashi, Renee Komorowski, Qingyian Liu, Guy Matsumoto, David J. St. Jean, Jr., Stefania Ursu, Murielle Vniant, Guifen Xu, Qiuping Ye, Chester Yuan, Jiandong Zhang, Xiping Zhang, Hua Tu and Minghan Wang
Further Studies with the 2-Amino-1,3-thiazol-4(5H)-one Class of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors: Reducing Pregnane X Receptor Activity and Exploring Activity in a Monkey Pharmacodynamic Model
Pursuing the same target as in the article described above (Hua, T., et al.), additional inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are disclosed by scientists at Amgen. All of the targets described contain a 2-amino-1,3-thiazol-4(5H)-one core. In order to introduce an aromatic ring directly onto the 5-position of the thiazolone, 1-(4-bromo-phenyl)-cyclopropanecarbonitrile (BioBlocks CP043) was cross-coupled with 2-[1-(4-fluoro-phenyl)-ethylamino]-5-methyl-thiazol-4-one using LiHMDS, Pd2(dba)3, and BINAP. The nitrile was then converted to the thiazolone phenyl-cyclopropylcarboxamide 11β-HSD1 inhibitor.
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| 4. |
Mirko Buchholz, Ulrich Heiser, Stephan Schilling, Andre' J. Niestroj, Katrin Zunkel, and Hans-Ulrich Demuth
The First Potent Inhibitors for Human Glutaminyl Cyclase: Synthesis and Structure-Activity Relationship
Mirko Buchholz and co-workers at Probiodrug (Germany) describe the first effective inhibitors for human glutaminyl cyclase (QC). The authors suggest that human QC might be involved in the pathophysiological process of Alzheimer's
disease, indicating a new potential drug target. Numerous examples are provided out of which one of the most potent contains a 3,4-dimethoxy-phenyl-cyclopropyl-thioamide moeity. Beginning with 1-(3,4-dimethoxy-phenyl)-cyclopropanecarbonitrile (BioBlocks CP062) hydrolysis to the acid (BioBlocks CP022), amide coupling and conversion to the thioamide with Lawesson's reagent affords the potent phenyl-cyclopropylthioamide QC inhibitor.
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