Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10595194 | Bioorganic & Medicinal Chemistry Letters | 2012 | 4 Pages |
Abstract
A single crystal was obtained of a lead B-RafV600E 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-RafV600E.
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Authors
Steve Wenglowsky, David Moreno, Joachim Rudolph, Yingqing Ran, Kateri A. Ahrendt, Alisha Arrigo, Ben Colson, Susan L. Gloor, Gregg Hastings,