4YES

Thrombin in complex with (S)-(4-chloro-2-((1-(5-methyl-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamido)methyl)phenyl)methanaminium

Summary for 4YES

• Entry DOI: 10.2210/pdb4yes/pdb
• Related PRD ID: PRD_002146
• Descriptor: Thrombin light chain, Thrombin heavy chain, Hirudin, ... (8 entities in total)
• Functional Keywords: sulfo-hirudin, inhibitor, complex, thrombin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted, extracellular space: P00734 P00734; Secreted: P01050
• Total number of polymer chains: 3
• Total formula weight: 36163.84

Authors

Orth, P. (deposition date: 2015-02-24, release date: 2015-06-17, Last modification date: 2024-11-06)

Primary citation

Chobanian, H.R.,Pio, B.,Guo, Y.,Shen, H.,Huffman, M.A.,Madeira, M.,Salituro, G.,Terebetski, J.L.,Ormes, J.,Jochnowitz, N.,Hoos, L.,Zhou, Y.,Lewis, D.,Hawes, B.,Mitnaul, L.,O'Neill, K.,Ellsworth, K.,Wang, L.,Biftu, T.,Duffy, J.L.
Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement.
Acs Med.Chem.Lett., 6:553-557, 2015

PubMed Abstract: Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.

PubMed: 26005532
DOI: 10.1021/acsmedchemlett.5b00047

Experimental method

X-RAY DIFFRACTION (1.5 Å)