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

被引：19

作者：

Abrahamsson, K. ^{[1
]}

Andersson, P. ^{[2
]}

Bergman, J. ^{[1
]}

Bredberg, U. ^{[1
]}

Branalt, J. ^{[1
]}

Egnell, A. -C. ^{[1
]}

Eriksson, U. ^{[1
]}

Gustafsson, D. ^{[1
]}

Hoffman, K. -J. ^{[1
]}

Nielsen, S. ^{[1
]}

Nilsson, I. ^{[1
]}

Pehrsson, S. ^{[1
]}

Polla, M. O. ^{[1
]}

Skjaeret, T. ^{[1
]}

Strimfors, M. ^{[1
]}

Wern, C. ^{[1
]}

Olwegard-Halvarsson, M. ^{[1
]}

Ortengren, Y. ^{[1
]}

机构：

[1] AstraZeneca R&D, Cardiovasc & Metab Disorders iMed, SE-43183 Molndal, Sweden

[2] AstraZeneca R&D, Drug Safety & Metab, SE-43183 Molndal, Sweden

来源：

MEDCHEMCOMM | 2016年 / 7卷 / 02期

关键词：

STRUCTURE-BASED DESIGN; TOTAL HIP-REPLACEMENT; POTENT; OPTIMIZATION; ABSORPTION; PHARMACODYNAMICS; RECEPTORS; RATS; DOGS;

D O I：

10.1039/c5md00479a

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：272 / 281

页数：10

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