Structure-Based Design, Synthesis, and Structure−Activity Relationship Studies of Novel Non-nucleoside Adenosine Deaminase Inhibitors

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 dru...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-07, Vol.47 (15), p.3730-3743
Main Authors: Terasaka, Tadashi, Kinoshita, Takayoshi, Kuno, Masako, Seki, Nobuo, Tanaka, Kohichiro, Nakanishi, Isao
Format: Article
Language:English
Subjects:
Adenosine Deaminase - chemistry
Adenosine Deaminase Inhibitors
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacokinetics
Amides - pharmacology
Animals
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Crystallography, X-Ray
Drug Design
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacokinetics
Indoles - pharmacology
Male
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Urea - chemistry
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0306374