1UML

Crystal structure of adenosine deaminase complexed with a potent inhibitor FR233624

Summary for 1UML

• Entry DOI: 10.2210/pdb1uml/pdb
• Related: 1O5R
• Descriptor: Adenosine deaminase, ZINC ION, 1-((1R)-1-(HYDROXYMETHYL)-3-{6-[(3-PHENYLPROPANOYL)AMINO]-1H-INDOL-1-YL}PROPYL)-1H-IMIDAZOLE-4-CARBOXAMIDE, ... (4 entities in total)
• Functional Keywords: beta barrel, zinc, hydrolase
• Biological source: Bos taurus (cattle)
• Cellular location: Cell membrane ; Peripheral membrane protein ; Extracellular side : P56658
• Total number of polymer chains: 1
• Total formula weight: 40852.60

Authors

Kinoshita, T. (deposition date: 2003-10-03, release date: 2004-09-21, Last modification date: 2023-12-27)

Primary citation

Terasaka, T.,Kinoshita, T.,Kuno, M.,Seki, N.,Tanaka, K.,Nakanishi, I.
Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors
J.Med.Chem., 47:3730-3743, 2004

PubMed Abstract: We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively. To utilize the newly formed hydrophobic space (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a simple phenyl ring (4c) was tolerated in terms of binding activity, and the length of the methylene-spacer was shown to be optimal at two or three. Replacement of an amide with an ether as a linker was also well tolerated in terms of binding activity and moreover improved the oral absorption (6a and 6b). Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a novel highly potent and orally bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl]imidazole-4-carboxamide 8c.

PubMed: 15239652
DOI: 10.1021/jm0306374

Experimental method

X-RAY DIFFRACTION (2.5 Å)