Open AccessDesign and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors
Author(s) -
Jeremy M. Richter,
Daniel L. Cheney,
Jay Bates,
Anzhi Wei,
Joseph M. Luettgen,
Alan R. Rendina,
Timothy M. Harper,
R. Narayanan,
Pancras C. Wong,
Dietmar Seiffert,
Ruth R. Wexler,
E. Scott Priestley
Publication year - 2016
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.6b00375
Subject(s) - metabolic stability , chemistry , combinatorial chemistry , stereochemistry , pharmacology , in vitro , biochemistry , medicine
Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa K i was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.