Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide PMID: 21438541

Target-related Cytokines

2026-09-23

Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

J Med Chem. 2011 May 12;54(9):3368-85. doi: 10.1021/jm200128m.

Luke Zehnder ¹ , Michael Bennett , Jerry Meng , Buwen Huang , Sacha Ninkovic , Fen Wang , John Braganza , John Tatlock , Tanya Jewell , Joe Zhongxiang Zhou , Ben Burke , Jeff Wang , Karen Maegley , Pramod P Mehta , Min-Jean Yin , Ketan S Gajiwala , Michael J Hickey , Shinji Yamazaki , Evan Smith , Ping Kang , Anand Sistla , Elena Dovalsantos , Michael R Gehring , Robert Kania , Martin Wythes , Pei-Pei Kung

Affiliations

Abstract

A novel class of heat shock protein 90 (HSP90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a Melanoma A2058 xenograft tumor model, and attractive DMPK profiles.