867267-27-4Relevant academic research and scientific papers
Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin
Metcalf, Brian,Chuang, Chihyuan,Dufu, Kobina,Patel, Mira P.,Silva-Garcia, Abel,Johnson, Carl,Lu, Qing,Partridge, James R.,Patskovska, Larysa,Patskovsky, Yury,Almo, Steven C.,Jacobson, Matthew P.,Hua, Lan,Xu, Qing,Gwaltney, Stephen L.,Yee, Calvin,Harris, Jason,Morgan, Bradley P.,James, Joyce,Xu, Donghong,Hutchaleelaha, Athiwat,Paulvannan, Kumar,Oksenberg, Donna,Li, Zhe
, p. 321 - 326 (2017/03/17)
We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ～150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).
SUBSTITUTED HETEROARYL ALDEHYDE COMPOUNDS AND METHODS FOR THEIR USE IN INCREASING TISSUE OXYGENATION
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, (2015/12/25)
Provided are substituted heteroaryl aldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating disorders mediate by hemoglobin and disorders that would benefit from increased tissue oxygenation.
Compounds and uses thereof for the modulation of hemoglobin
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, (2014/09/30)
Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
Compounds and uses thereof for the modulation of hemoglobin
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, (2014/09/29)
Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
INHIBITORS OF THE KYNURENINE PATHWAY
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, (2014/12/12)
The present application provides novel inhibitors of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase, metabolites thereof, and phannaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. A therapeutically effective amount of one or more of the compounds of formula (I) is useful in treating diseases resulting from dysregulation of the kynurenine pathway. Compounds of formula (I) act by inhibiting the enzymatic activity or expression of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase.
SUBSTITUTED HETEROARYL ALDEHYDE COMPOUNDS AND METHODS FOR THEIR USE IN INCREASING TISSUE OXYGENATION
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, (2013/07/19)
Provided are substituted heteroaryl aldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating disorders mediate by hemoglobin and disorders that would benefit from increased tissue oxygenation.
A regioselective route to 5- and 6-azaindoles
Lomberget, Thierry,Radix, Sylvie,Barret, Roland
, p. 2080 - 2082 (2007/10/03)
The synthesis of 4,7-dimethoxy 5- and 6-azaindoles, a structural unit that is present in recently developed anti-HIV-1 agents, was achieved in a regioselective manner. The developed strategy is based on the appropriate choice of a protecting group during a lithium-mediated formylation step, followed by thermal cyclization of azidoacrylates. Georg Thieme Verlag Stuttgart.
