4YZU

Rapid development of two Factor IXa inhibitors from Hit to Lead

Summary for 4YZU

• Entry DOI: 10.2210/pdb4yzu/pdb
• Related: 4Z0K
• Descriptor: Coagulation factor IX, N-[2-(5,6-dimethyl-1H-benzimidazol-2-yl)ethyl]-4-(4H-1,2,4-triazol-4-yl)benzamide, SODIUM ION, ... (7 entities in total)
• Functional Keywords: serine proteinase, blood coagulation, coagulation factor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted : P00740 P00740
• Total number of polymer chains: 2
• Total formula weight: 33572.66

Authors

Hruza, A.,Reichert, P. (deposition date: 2015-03-25, release date: 2015-05-20, Last modification date: 2024-10-23)

Primary citation

Parker, D.L.,Walsh, S.,Li, B.,Kim, E.,Sharipour, A.,Smith, C.,Chen, Y.H.,Berger, R.,Harper, B.,Zhang, T.,Park, M.,Shu, M.,Wu, J.,Xu, J.,Dewnani, S.,Sherer, E.C.,Hruza, A.,Reichert, P.,Geissler, W.,Sonatore, L.,Ellsworth, K.,Balkovec, J.,Greenlee, W.,Wood, H.B.
Rapid development of two factor IXa inhibitors from hit to lead.
Bioorg.Med.Chem.Lett., 25:2321-2325, 2015

PubMed Abstract: Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.

PubMed: 25937013
DOI: 10.1016/j.bmcl.2015.04.025

Experimental method

X-RAY DIFFRACTION (1.41 Å)