Structure-Based Design and Synthesis of Non-Nucleoside, Potent, and Orally Bioavailable Adenosine Deaminase Inhibitors

We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K i = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K i = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-05, Vol.47 (11), p.2728-2731
Main Authors: Terasaka, Tadashi, Okumura, Hiroyuki, Tsuji, Kiyoshi, Kato, Takeshi, Nakanishi, Isao, Kinoshita, Takayoshi, Kato, Yasuko, Kuno, Masako, Seki, Nobuo, Naoe, Yoshinori, Inoue, Takeshi, Tanaka, Kohichiro, Nakamura, Katsuya
Format: Article
Language:English
Subjects:
Adenosine Deaminase Inhibitors
Administration, Oral
Animals
Antineoplastic agents
Biological and medical sciences
Biological Availability
Bones, joints and connective tissue. Antiinflammatory agents
Crystallography, X-Ray
Dogs
Drug Design
General aspects
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
In Vitro Techniques
Medical sciences
Microsomes, Liver - metabolism
Models, Molecular
Molecular Structure
Naphthalenes - chemical synthesis
Naphthalenes - chemistry
Naphthalenes - pharmacology
Pharmacology. Drug treatments
Rats
Structure-Activity Relationship
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Summary:We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K i = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K i = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered two inhibitors with improved oral bioavailability [6 (K i = 13 nM, BA = 44%) and 7 (K i = 9.8 nM, BA = 42%)]. 6 demonstrated in vivo efficacy in models of inflammation and lymphoma.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0499559