6ZUW

Crystal Structure of Thrombin in complex with compound40

Summary for 6ZUW

• Entry DOI: 10.2210/pdb6zuw/pdb
• Descriptor: Prothrombin, Hirudin-2, [2-[[(1~{R})-1-(3-chlorophenyl)ethyl]amino]-7-methoxy-1,3-benzoxazol-5-yl]-[(2~{S},5~{R})-5-ethyl-2-(2-hydroxyethyl)-2-methyl-morpholin-4-yl]methanone, ... (6 entities in total)
• Functional Keywords: coagulation, blood clotting, convertion of fibrinogen to fibrin, blood clotting inhibitor, thrombin inhibitor, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 36020.41

Authors

Schafer, M. (deposition date: 2020-07-23, release date: 2020-08-26, Last modification date: 2024-11-06)

Primary citation

Hillisch, A.,Gericke, K.M.,Allerheiligen, S.,Roehrig, S.,Schaefer, M.,Tersteegen, A.,Schulz, S.,Lienau, P.,Gnoth, M.,Puetter, V.,Hillig, R.C.,Heitmeier, S.
Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics.
J.Med.Chem., 63:12574-12594, 2020

PubMed Abstract: Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.

PubMed: 33108181
DOI: 10.1021/acs.jmedchem.0c01035

Experimental method

X-RAY DIFFRACTION (2 Å)