Optimization of small molecule agonists of the thrombopoietin (Tpo) receptor derived from a benzo[a]carbazole hit scaffold.
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.
Marsilje
Thomas H
TH
Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA. TMarsilje@gnf.org
Alper
Phil B
PB
Lu
Wenshuo
W
Mutnick
Daniel
D
Michellys
Pierre-Yves
PY
He
Yun
Y
Karanewsky
Donald S
DS
Chow
Donald
D
Gerken
Andrea
A
Lao
Jianmin
J
Kim
Min-Ju
MJ
Seidel
H Martin
HM
Tian
Shin-Shay
SS
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
D001555:Benzene Derivatives; D002227:Carbazoles; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin