title: Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists.
abstract: An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
authors.affiliation: Pfizer Worldwide Research & Development , San Diego, CA 92121, USA. Alex.Guo@pfizer.com
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Susan
authors.initials: S
authors.lastname: Kephart
authors.forename: Martha
authors.initials: M
authors.lastname: Ornelas
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.forename: Asako
authors.initials: A
authors.lastname: Nagata
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burke
authors.forename: Martin
authors.initials: M
authors.lastname: Edwards
authors.forename: Natilie
authors.initials: N
authors.lastname: Hosea
authors.forename: Ping
authors.initials: P
authors.lastname: Kang
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.forename: Jon
authors.initials: J
authors.lastname: Engebretsen
authors.forename: David
authors.initials: D
authors.lastname: Briere
authors.forename: Manli
authors.initials: M
authors.lastname: Shi
authors.forename: Hovik
authors.initials: H
authors.lastname: Gukasyan
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Kevin
authors.initials: K
authors.lastname: Dack
authors.forename: Toby
authors.initials: T
authors.lastname: Underwood
authors.forename: Patrick
authors.initials: P
authors.lastname: Johnson
authors.forename: Andrew
authors.initials: A
authors.lastname: Morell
authors.forename: Robert
authors.initials: R
authors.lastname: Felstead
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kuruma
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsimoto
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Fanjul
mesh_terms: D000284:Administration, Oral; D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000728:Androgens / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003503:Cyclobutanes; D008024:Ligands; C569676:N,N-(3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-(methylamino)-2-oxoethyl)-1H-pyrazole-3-carboxamide; C569677:N-(3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)imidazo(1,2-a)pyrimidine-3-carboxamide; D011720:Pyrazoles