title: Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors.
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.
authors.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
authors.forename: Tadashi
authors.initials: T
authors.lastname: Terasaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okumura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tsuji
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kato
authors.forename: Isao
authors.initials: I
authors.lastname: Nakanishi
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kato
authors.forename: Masako
authors.initials: M
authors.lastname: Kuno
authors.forename: Nobuo
authors.initials: N
authors.lastname: Seki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Naoe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nakamura
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; 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; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058892:Adenosine Deaminase Inhibitors; D007093:Imidazoles; D009281:Naphthalenes