Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone.
The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.
Kung
Pei-Pei
PP
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA. peipei.kung@pfizer.com
Huang
Buwen
B
Zhang
Gang
G
Zhou
Joe Zhongxiang
JZ
Wang
Jeff
J
Digits
Jennifer A
JA
Skaptason
Judith
J
Yamazaki
Shinji
S
Neul
David
D
Zientek
Michael
M
Elleraas
Jeff
J
Mehta
Pramod
P
Yin
Min-Jean
MJ
Hickey
Michael J
MJ
Gajiwala
Ketan S
KS
Rodgers
Caroline
C
Davies
Jay F
JF
Gehring
Michael R
MR
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D054833:Isoindoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles