title: Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
abstract: The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.|Oncology iMed, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: De Savi
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Rabow
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Norman
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Camila
authors.initials: C
authors.lastname: de Almeida
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Buttar
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Rowena J
authors.initials: RJ
authors.lastname: Callis
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Currie
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Curwen
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Davies
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Donald
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Lyman J L
authors.initials: LJ
authors.lastname: Feron
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Helen
authors.initials: H
authors.lastname: Gingell
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Glossop
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Hayter
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Syeed
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Galith
authors.initials: G
authors.lastname: Karoutchi
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lamont
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Philip
authors.initials: P
authors.lastname: MacFaul
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moss
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Pearson
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Michael
authors.initials: M
authors.lastname: Tonge
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Graeme E
authors.initials: GE
authors.lastname: Walker
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Weir
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
authors.forename: Zena
authors.initials: Z
authors.lastname: Wilson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry* / Q000378:metabolism*; D017321:Clinical Trials, Phase I as Topic; D015536:Down-Regulation / Q000187:drug effects; D015195:Drug Design; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D007273:Injections, Intramuscular; D014961:X-Ray Diffraction
chemical_list: C000604573:AZD9496; D000970:Antineoplastic Agents; D002934:Cinnamates; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D007211:Indoles