The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs

Nigel S Watson; Carl Adams; David Belton; David Brown; Cynthia L Burns-Kurtis; Laiq Chaudry; Chuen Chan; Máire A Convery; David E Davies; Anne M Exall; John D Harling; Stephanie Irvine; Wendy R Irving; Savvas Kleanthous; Iain M McLay; Anthony J Pateman; Angela N Patikis; Theresa J Roethke; Stefan Senger; Gary J Stelman; John R Toomey; Robert I West; Caroline Whittaker; Ping Zhou; Robert J Young

doi:10.1016/j.bmcl.2011.01.129

The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1588-92. doi: 10.1016/j.bmcl.2011.01.129. Epub 2011 Feb 2.

Affiliation

¹ GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom.

PMID: 21349711
DOI: 10.1016/j.bmcl.2011.01.129

Abstract

The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.

MeSH terms

Administration, Oral
Animals
Benzazepines / administration & dosage
Benzazepines / chemical synthesis*
Benzazepines / pharmacology
Crystallography, X-Ray
Drug Evaluation, Preclinical
Factor Xa Inhibitors*
Molecular Structure
Rats
Serine Proteinase Inhibitors / administration & dosage
Serine Proteinase Inhibitors / chemistry*
Tetrahydroisoquinolines / administration & dosage
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / pharmacology

Substances

Benzazepines
Factor Xa Inhibitors
Serine Proteinase Inhibitors
Tetrahydroisoquinolines