Thrombin inhibitors design/discovery

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. 

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... 

Neumann, T, Junker, H.-D., Keil, O., Burkert, K., Ottleben, H., Gamer, J., Sekul, R., Deppe, H., Feurer, A., Tomandl, D., Metz, G. Discovery of thrombin inhibitor fragments from chemical microarray screening. Lett. Drug Design Discov. 2005, 2, 590-594. 

A very successful progressive design approach for thrombin is to start from a small building block, known or expected to bind non-covalently in a precise position in the active site, and expand this by progressive addition of substituents. We have called such building blocks needles and have described the discovery of a thrombin-specific needle and its evolution to a full-blown thrombin inhibitor with the use of sequential X-ray structural analyses (see [28]). The details will not be repeated here. The inhibitor, napsagatran, 5 is shown in Fig. 7.5. 

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