Rational design of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors: predicting enzyme conformational change and metabolism.
From metabolic considerations and prediction of an inhibitor-induced conformational change, novel adenosine deaminase (ADA) inhibitors with improved activities and oral bioavailability have been developed on the basis of our originally designed non-nucleoside ADA inhibitors. They demonstrated in vivo efficacy in models of inflammation and lymphoma. Furthermore, X-ray crystal structure analysis has revealed a novel induced fit to ADA.
Terasaka
Tadashi
T
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. tadashi.terasaka@jp.astellas.com
Tsuji
Kiyoshi
K
Kato
Takeshi
T
Nakanishi
Isao
I
Kinoshita
Takayoshi
T
Kato
Yasuko
Y
Kuno
Masako
M
Inoue
Takeshi
T
Tanaka
Kohichiro
K
Nakamura
Katsuya
K
D000243:Adenosine Deaminase / Q000737:chemistry / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
D058892:Adenosine Deaminase Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D007093:Imidazoles; D000243:Adenosine Deaminase