title: Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153).
abstract: Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Rowena
authors.initials: R
authors.lastname: Callis
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Carr
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Huawei
authors.initials: H
authors.lastname: Chen
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Edwin
authors.initials: E
authors.lastname: Clark
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Lyman
authors.initials: L
authors.lastname: Feron
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Steve
authors.initials: S
authors.lastname: Glossop
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Graham
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Maureen
authors.initials: M
authors.lastname: Hattersley
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lamont
authors.affiliation: AstraZeneca , Chemin du Moulin de Vrilly, 51100 Reims, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Ouvry
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Anil
authors.initials: A
authors.lastname: Patel
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Joe
authors.initials: J
authors.lastname: Patel
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Rabow
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Roberts
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Stokes
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Natalie
authors.initials: N
authors.lastname: Stratton
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Graeme E
authors.initials: GE
authors.lastname: Walker
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Whalley
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Whittaker
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: Gail
authors.initials: G
authors.lastname: Wrigley
authors.affiliation: AstraZeneca, Mereside , Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.|Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waring
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D018938:Caco-2 Cells; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D004285:Dogs; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D011720:Pyrazoles; D011724:Pyridazines; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006574:Heterocyclic Compounds, 2-Ring; D009687:Nuclear Proteins; D010879:Piperazines; D011720:Pyrazoles; D011724:Pyridazines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000621120:AZD5153