Structure-Based Design, Synthesis, and Structure−Activity Relationship Studies of Novel Non-nucleoside Adenosine Deaminase Inhibitors
| Autor: | Kohichiro Tanaka, Tadashi Terasaka, Masako Kuno, Isao Nakanishi, Nobuo Seki, Takayoshi Kinoshita |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Models Molecular Benzimidazole Indoles Adenosine Deaminase Stereochemistry Crystallography X-Ray Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Adenosine deaminase Drug Discovery Adenosine Deaminase Inhibitors Animals Urea Structure–activity relationship biology Bicyclic molecule Imidazoles Amides Rats chemistry Enzyme inhibitor Drug Design biology.protein Molecular Medicine Adenosine Deaminase Inhibitor Linker Nucleoside |
| Zdroj: | Journal of Medicinal Chemistry. 47:3730-3743 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0306374 |
| Popis: | We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively. To utilize the newly formed hydrophobic space (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a simple phenyl ring (4c) was tolerated in terms of binding activity, and the length of the methylene-spacer was shown to be optimal at two or three. Replacement of an amide with an ether as a linker was also well tolerated in terms of binding activity and moreover improved the oral absorption (6a and 6b). Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a novel highly potent and orally bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl]imidazole-4-carboxamide 8c. |
| Databáze: | OpenAIRE |
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