title: Solution-phase parallel synthesis of Hsp90 inhibitors.
abstract: 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.
authors: Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.
authors: Sujin
authors: S
authors: Cho-Schultz
authors: Monica Jo
authors: MJ
authors: Patten
authors: Buwen
authors: B
authors: Huang
authors: Jeff
authors: J
authors: Elleraas
authors: Ketan S
authors: KS
authors: Gajiwala
authors: Michael J
authors: MJ
authors: Hickey
authors: Jeff
authors: J
authors: Wang
authors: Pramod P
authors: PP
authors: Mehta
authors: Ping
authors: P
authors: Kang
authors: Michael R
authors: MR
authors: Gehring
authors: Pei-Pei
authors: PP
authors: Kung
authors: Scott C
authors: SC
authors: Sutton
mesh_terms: 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
chemical_list: D020719:Glucuronides; D018841:HSP90 Heat-Shock Proteins