title: Optimization of small molecule agonists of the thrombopoietin (Tpo) receptor derived from a benzo[a]carbazole hit scaffold.
abstract: The lead optimization of a novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. The chemical instability of the dihydro-benzo[a]carbazole lead 2 was successfully addressed in the design and evaluation of compounds which also demonstrated improved potency compared to 2. Members of the scaffold have been identified which are full agonists that demonstrate cellular functional potency <50 nM. Analog 21 demonstrates equivalent efficacy in the human megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag.
authors.affiliation: Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA. TMarsilje@gnf.org
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.forename: Phil B
authors.initials: PB
authors.lastname: Alper
authors.forename: Wenshuo
authors.initials: W
authors.lastname: Lu
authors.forename: Daniel
authors.initials: D
authors.lastname: Mutnick
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: Donald
authors.initials: D
authors.lastname: Chow
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerken
authors.forename: Jianmin
authors.initials: J
authors.lastname: Lao
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.forename: Shin-Shay
authors.initials: SS
authors.lastname: Tian
mesh_terms: D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008533:Megakaryocytes / Q000378:metabolism; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013926:Thrombopoietin / Q000737:chemistry / Q000378:metabolism
chemical_list: D001555:Benzene Derivatives; D002227:Carbazoles; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin