Discovery of AZD8165 – a clinical candidate from a novel series of neutral thrombin inhibitors

K. Abrahamsson; P. Andersson; J. Bergman; U. Bredberg; J. Brånalt; A.-C. Egnell; U. Eriksson; D. Gustafsson; K.-J. Hoffman; S. Nielsen; I. Nilsson; S. Pehrsson; M. O. Polla; T. Skjaeret; M. Strimfors; C. Wern; M. Ölwegård-Halvarsson; Y. Örtengren

doi:10.1039/C5MD00479A

Discovery of AZD8165 – a clinical candidate from a novel series of neutral thrombin inhibitors†

K. Abrahamsson,^a P. Andersson,^b J. Bergman,^a U. Bredberg,^a J. Brånalt,^a A.-C. Egnell,^a U. Eriksson,^a D. Gustafsson,^a K.-J. Hoffman,^a S. Nielsen,^a I. Nilsson,^a S. Pehrsson,^a M. O. Polla,*^a T. Skjaeret,^a M. Strimfors,^a C. Wern,^a M. Ölwegård-Halvarsson^a and Y. Örtengren^a

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* Corresponding authors

^a Cardiovascular and Metabolic Disorders iMed, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden
E-mail: magnus.polla@astrazeneca.com

^b Drug Safety and Metabolism, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden

Abstract

A novel series of neutral thrombin inhibitors has been developed using a selection process based on docking experiments and property calculations and predictions. This work resulted in the identification of the highly potent thrombin inhibitor compound 85 (K_i = 300 pM) and the corresponding propionate prodrug 5 (AZD8165) as a candidate for clinical evaluation in the treatment of thrombosis and related diseases. AZD8165 was found to be safe and well tolerated and delivered the expected pharmacological response in a phase I trial in healthy male volunteers.

MedChemComm

Discovery of AZD8165 – a clinical candidate from a novel series of neutral thrombin inhibitors†

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Discovery of AZD8165 – a clinical candidate from a novel series of neutral thrombin inhibitors

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