Thrombin inhibitors design

Frederick, R. Robert, S. Charlier, C. de Ruyck, J. Wouters, J. Masereel, B. Pochet, L. Mechanism-based thrombin inhibitors design, synthesis, and molecular docking of a new selective 2-OXO-2/7- l-benzopyxan derivative. J. Med. Chem. 2007, 50, 3645-3650. 

Sanderson P E J, Naylor-Olsen A M (1998). Thrombin inhibitor design. Curr. Med. Chem. 5 289-304. 

Bohm HJ, Banner DW, Weber L. Combinatorial docking and combinatorial chemistry design of potent non-peptide thrombin inhibitors. J Comput Aided Mol Design 1999 13 51-6. 

Salzet, M. 2002. Leech thrombin inhibitors. Current Pharmaceutical Design 8(7), 493-503. 

Substrate for the design of thrombin inhibitors 1999BML913, 1997TL8807... 

S. D., Lucas, B.J., Gardell, S.J., Lyle, E.A., Appleby, S.D., Cook, J.J., FIolahan, M.A., Stranieri, M.T., Lynch,Y J., Lin, J.H., Chen, I.W., Vastag, K., Naylor-Olsen, A.M., and Vacca, J.P. Discovery and development of the novel potent orally active thrombin inhibitor N-(9-Hydroxy-9-fluorenecarboxy)prolyl tran s -4-amin ocycl ohexylmethyl ami de (L-372,460) coapplication of structure-based design and rapid multiple analog synthesis on solid support. 

Linusson, a., Gotteries, )., Olsson, T., Oernskov, E., Folestad, S., Noeden, B., and Wold, S. Statistical molecular design, parallel synthesis, and biological evaluation of a library of thrombin inhibitors. /. Med. Chem. 2001, 44, 3424-3439. 

Discovery of therapeutically effective thrombin inhibitors involves issues such as affinity and selectivity, bioavailability, and formulation. In addition to these relatively common concerns, the complex in vivo mechanisms designed to... 

Obst U, Gramlich V, Diederich F, Weber L, Banner DW. Design of novel, nonpeptidic thrombin inhibitors and structure of a thrombin-inhibitor complex. Angew Chem Int Ed Engl 1995 34 1739. 

Tsuda Y, Cygler M, Gibbs BF, Pedyczak A, Fethiere J, Yue SY, Konishi Y. Design of potent bivalent thrombin inhibitors based on hirudin sequence incorporation of nonsubstrate-type active site inhibitors. Biochemistry 1994 33 14443-14451. 

Szewczuk Z, Gibbs BF, Yue SY, Purisima E, Zdanvo A, Cygler M, Konishi Y. Design of a linker for trivalent thrombin inhibitors interaction of the main chain of the linker with thrombin. Biochemistry 1993 32 3396-3404. 

Hilpert , Ackermann J, Banner DW, Gast A, Gubemator K, Hadvary P, Labler L, Muller K, Schmid G, Tschopp T, van de Waterbeemd H. Design and synthesis of potent and highly selective thrombin inhibitors. J Med Chem 1994 37 3889-3901. 

A second example of protease inhibitor design that properly illustrates the peptide scaffold-based approach is that of thrombin inhibitors. Work with these compounds led to the identification of highly potent, selective, and in vivo-effective lead compounds. A member of the serine protease family, thrombin cleaves a number of substrates (e.g., fibrinogen) and activates its platelet receptor (a G-protein-coupled receptor) by proteolysis of the extracellular N-terminal domain which results in self-activation (for a review see Reference 66). Initial lead inhibitors of thrombin were substrate-based, including the fibrinogen P3-Pi Phe-Pro-Arg sequence [67] and simple Arg derivatives such as Tos-Arg-OMe [68]. 

Protease 3D structural models thrombin-inhibitor complex and drug design... 

Peptide chimeras of this type have proven extremely valuable for the examination of an array of recognition events. In conjunction with molecular modeling, peptidomimetic substrates and inhibitors of human thrombin were designed and synthesized to evaluate our proposed structure for the thrombin-bound conformation of fibrinopeptide A (Scheme 2i)J%]... 

In another example of combinatorial parallel chemistry, we have recently used the Ugi three-component reactions (Ugi 3-CR) to construct a library of 16,840 protease inhibitors (25). It has been demonstrated previously that the Ugi-3CR reaction provides a useful chemical scaffold for the design of serine protease inhibitors N-substituted 2-substituted-glycine /V-ary 1/alky 1 -amidcs have been identified that are potent factor Xa, factor Vila, or thrombin inhibitors. The three variable substituents of this scaffold, provided by the amine, aldehyde, and isonitrile starting materials, span a favorable pyramidal pharma-cophoric scaffold that can fill the S1, S2, and S3 pockets of the respective protease. This library was screened against five proteases (factor Xa, trypsin, uro-... 

Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002 45 1757-1766. 

The interesting macrocyclic pentapeptide scaffold prompted several research groups to design new total synthesis routes for cydotheonamide [40,41a,b,43] and derivatives thereof [44], mainly for SAR-studies for targeting the development of novel synthetic thrombin inhibitors. The first total synthesis of CtB 20 was published by Hagihara and Schreiber [40]. This synthesis (Scheme 1.2) defined the true stereochemical structure of cydotheonamide, which had previously been reported incorrectly. 

Combinatorial Docking and Combinatorial Chemistry Design of Potent Non-Peptide Thrombin Inhibitors. 

Recognition at the Thrombin Active Site Structure-Based Design and Synthesis of Potent and Selective Thrombin Inhibitors and the X-Ray Crystal Structures of Two Thrombin-Inhibitor Complexes. 

Grootenhuis, /. Comput.-Aided Mol. Design, 13, 167 (1999). Comparison of Two Implementations of the Incremental Construction Algorithm in Flexible Docking of Thrombin Inhibitors. 

The thrombin-inhibitor example demonstrates a path from the bioactive 3-D struc-tnre of a peptide to small molecules. However, unambiguous structural information on the bioactive ligand conformation needed for snch a transformation is only available in a limited nnmber of cases. In most cases, additional complementary information has to be nsed to deduce the bioactive conformation of a bonnd ligand, and thns a pharmacophore model for virtual screening or design. 

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