Solution-phase parallel synthesis of Hsp90 inhibitors.
As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library of racemic resorcinol amides was prepared affording 131 purified compounds. After evaluation in a binding assay, followed by an AKT-Luminex cellular assay, three potent analogs had functional activity between 0.1 and 0.3 microM. Resolution by preparative chiral SFC chromatography led to (+)-15, (+)-16, and (+)-17 having functional IC(50) = 27, 43, and 190 nM, respectively. (+)-15 exhibited high clearance in human hepatocytes driven primarily by glucuronidation as confirmed by metabolite identification. A second 8 x 14 exploratory library was designed to investigate heterocyclic replacements of the resorcinol ring. The second library highlights the use of the (-)-sparteine-mediated enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine to prepare chiral 2-arylpyrrolidines in parallel.
Cho-Schultz
Sujin
S
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.
Patten
Monica Jo
MJ
Huang
Buwen
B
Elleraas
Jeff
J
Gajiwala
Ketan S
KS
Hickey
Michael J
MJ
Wang
Jeff
J
Mehta
Pramod P
PP
Kang
Ping
P
Gehring
Michael R
MR
Kung
Pei-Pei
PP
Sutton
Scott C
SC
D002850:Chromatography, Gel / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D020719:Glucuronides / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D010599:Pharmacokinetics; D011487:Protein Conformation
D020719:Glucuronides; D018841:HSP90 Heat-Shock Proteins