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Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors.

ABSTRACT: 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.

SUBMITTER: Richter JM

PROVIDER: S-EPMC5238462 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors.

Richter Jeremy M JM Cheney Daniel L DL Bates J Alex JA Wei Anzhi A Luettgen Joseph M JM Rendina Alan R AR Harper Timothy M TM Narayanan Rangaraj R Wong Pancras C PC Seiffert Dietmar D Wexler Ruth R RR Priestley E Scott ES

ACS medicinal chemistry letters 20161101 1

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 <i>K</i><sub>i</sub> was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability. ...[more]

PMID: 28105277

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