title: 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.
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.
authors: La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
authors: Luke
authors: L
authors: Zehnder
authors: Michael
authors: M
authors: Bennett
authors: Jerry
authors: J
authors: Meng
authors: Buwen
authors: B
authors: Huang
authors: Sacha
authors: S
authors: Ninkovic
authors: Fen
authors: F
authors: Wang
authors: John
authors: J
authors: Braganza
authors: John
authors: J
authors: Tatlock
authors: Tanya
authors: T
authors: Jewell
authors: Joe Zhongxiang
authors: JZ
authors: Zhou
authors: Ben
authors: B
authors: Burke
authors: Jeff
authors: J
authors: Wang
authors: Karen
authors: K
authors: Maegley
authors: Pramod P
authors: PP
authors: Mehta
authors: Min-Jean
authors: MJ
authors: Yin
authors: Ketan S
authors: KS
authors: Gajiwala
authors: Michael J
authors: MJ
authors: Hickey
authors: Shinji
authors: S
authors: Yamazaki
authors: Evan
authors: E
authors: Smith
authors: Ping
authors: P
authors: Kang
authors: Anand
authors: A
authors: Sistla
authors: Elena
authors: E
authors: Dovalsantos
authors: Michael R
authors: MR
authors: Gehring
authors: Robert
authors: R
authors: Kania
authors: Martin
authors: M
authors: Wythes
authors: Pei-Pei
authors: PP
authors: Kung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C559868:2-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; D000970:Antineoplastic Agents; D001798:Blood Proteins; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles; D011743:Pyrimidines