2. Academic Validation
  3. 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

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

Affiliation

  • 1 La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
PMID: 21438541 DOI: 10.1021/jm200128m
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.

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