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

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 .