Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s Tyrosine Kinase (BTK) inhibitor scaffold

doi:10.1016/j.bmcl.2014.11.030

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 2, 15 January 2015, Pages 367-371

https://doi.org/10.1016/j.bmcl.2014.11.030 Get rights and content

Abstract

A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.

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Acknowledgment

This work was supported exclusively by Hoffmann-La Roche.

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^†: Current address: Nurix, Inc., Medicinal Chemistry, 1700 Owens Street, Suite 290, San Francisco, CA 94158, United States.

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Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton’s Tyrosine Kinase (BTK) inhibitor scaffold

Abstract

Graphical abstract

Section snippets

Acknowledgment

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

J. Org. Chem.

J. Med. Chem.

Science

J. Med. Chem.

ChemBioChem

J. Med. Chem.

J. Pharmacol. Exp. Ther.

ChemBioChem