title: Discovery of 3-aryloxy-lactam analogs as potent androgen receptor full antagonists for treating castration resistant prostate cancer.
abstract: High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA. alex.guo@pfizer.com
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Susan
authors.initials: S
authors.lastname: Kephart
authors.forename: Martha
authors.initials: M
authors.lastname: Ornelas
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Asako
authors.initials: A
authors.lastname: Nagata
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.forename: Jeff
authors.initials: J
authors.lastname: Elleraas
authors.forename: Natilie
authors.initials: N
authors.lastname: Hosea
authors.forename: Jon
authors.initials: J
authors.lastname: Engebretsen
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Fanjul
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000601:surgery; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007769:Lactams; D011944:Receptors, Androgen