Pyrazolopyridine inhibitors of B-Raf(V600E). Part 3: an increase in aqueous solubility via the disruption of crystal packing.
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).
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Steve
S
Wenglowsky
David
D
Moreno
Joachim
J
Rudolph
Yingqing
Y
Ran
Kateri A
KA
Ahrendt
Alisha
A
Arrigo
Ben
B
Colson
Susan L
SL
Gloor
Gregg
G
Hastings
D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D014867:Water; D048493:Proto-Oncogene Proteins B-raf