4CR5

Creating Novel Activated Factor Xi Inhibitors Through Fragment Based Lead Generation and Structure Aided Drug Design.

(2015) PLoS One 10: 13705

• PubMed: 25629509 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1371/journal.pone.0113705
• Primary Citation of Related Structures:  
  4CR5, 4CR9, 4CRA, 4CRB, 4CRC, 4CRD, 4CRE, 4CRF, 4CRG


• PubMed Abstract: 
  

  Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.

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Organizational Affiliation: 

Medicinal Chemistry, Cardiovascular & Metabolic Diseases Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.