Download MendeleyStructure-Based Design and Synthesis of Non-Nucleoside, Potent, and Orally Bioavailable Adenosine Deaminase Inhibitors
Terasaka, T., Okumura, H., Tsuji, K., Kato, T., Nakanishi, I., Kinoshita, T., Kato, Y., Kuno, M., Seki, N., Naoe, Y., Inoue, T., Tanaka, K., Nakamura, K.(2004) J Med Chem 47: 2728-2731
- PubMed: 15139750
- DOI: https://doi.org/10.1021/jm0499559
- Primary Citation of Related Structures:
1V79, 1V7A, 2E1W - PubMed Abstract:
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.
Organizational Affiliation:
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. tadashi_terasaka@po.fujisawa.co.jp
