Brian Metcalf, Chihyuan Chuang, Kobina Dufu, Mira P Patel, Abel Silva-Garcia, Carl Johnson, Qing Lu, James R Partridge, Larysa Patskovska, Yury Patskovsky, Steven C Almo, Matthew P Jacobson, Lan Hua, Qing Xu, Stephen L Gwaltney, Calvin Yee, Jason Harris, Bradley P Morgan, Joyce James, Donghong Xu, Athiwat Hutchaleelaha, Kumar Paulvannan, Donna Oksenberg, Zhe Li
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...
March 9, 2017: ACS Medicinal Chemistry Letters