Pyrazolopyridine inhibitors of B-RafV600E. Part 3: An increase in aqueous solubility via the disruption of crystal packing

doi:10.1016/j.bmcl.2011.12.030

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 2, 15 January 2012, Pages 912-915

https://doi.org/10.1016/j.bmcl.2011.12.030 Get rights and content

Abstract

A single crystal was obtained of a lead B-Raf^V600E inhibitor with low aqueous solubility. The X-ray crystal structure revealed hydrogen-bonded head-to-tail dimers formed by the pyrazolopyridine and sulfonamide groups of a pair of molecules. This observation suggested a medicinal chemistry strategy to disrupt crystal packing and reduce the high crystal lattice energy of alternative inhibitors. Both a bulkier group at the interface of the dimer and an out-of-plane substituent were required to decrease the compound’s melting point and increase aqueous solubility. These substituents were selected based on previously developed structure–activity relationships so as to concurrently maintain good enzymatic and cellular activity against B-Raf^V600E.

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Acknowledgements

The authors thank Jaroslaw Mazurek from Avantium for determination of the crystal structure of 1 and Antonio DiPasquale from The University of California, Berkeley for determination of the crystal structure of 6. The authors also thank Kevin Hunt, Yvan LeHuerou, Li Ren, Stephen Schlachter, and Tony Tang for helpful discussions and support.

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Pyrazolopyridine inhibitors of B-RafV600E. Part 3: An increase in aqueous solubility via the disruption of crystal packing

Abstract

Graphical abstract

Section snippets

Acknowledgements

Biorg. Med. Chem. Lett.

J. Pharm. Sci.

ACS Med. Chem. Lett.

Mol. Pharm.

Nature

J. Med. Chem.

J. Med. Chem.

Bioorg. Med. Chem. Lett.

Pyrazolopyridine inhibitors of B-Raf^V600E. Part 3: An increase in aqueous solubility via the disruption of crystal packing