Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors.

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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

Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors.

J Med Chem. 2004 May 20;47(11):2728-31.

PubMed ID

15139750 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
1-{(1R,2S)-2-HYDROXY-1-[2-(2-NAPHTHYLOXY)ETHYL]PROPYL}-1H-IMIDAZONE-4-CARBOXAMIDE	Adenosine deaminase	Ki (nM)	9.8	7.4	22	Details
FR-234938	Adenosine deaminase	Ki (nM)	11	7.4	22	Details
FR239087	Adenosine deaminase	Ki (nM)	13	7.4	22	Details