1261295-05-9Relevant articles and documents
A hit deconstruction approach for the discovery of fetal hemoglobin inducers
Benowitz, Andrew B.,Eberl, H. Christian,Erickson-Miller, Connie L.,Gilmartin, Aidan G.,Gore, Elizabeth R.,Montoute, Monica N.,Wu, Zining
, p. 3676 - 3680 (2018/10/31)
Beta-hemoglobinopathies such as sickle cell disease represent a major global unmet medical need. De-repression of fetal hemoglobin in erythrocytes is a clinically validated approach for the management of sickle cell disease, but the only FDA-approved medicine for this purpose has limitations to its use. We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules with the ability to de-repress fetal hemoglobin, which resulted in the identification of the benzoxaborole-containing hit compound 1. This compound was found to have modest cellular potency and lead-like pharmacokinetics, but no identifiable SAR to enable optimization. Systematic deconstruction of a closely related analog of 1 revealed the fragment-like carboxylic acid 12, which was then optimized to provide tetrazole 31, which had approximately 100-fold improved cellular potency compared to 1, high levels of oral exposure in rats, and excellent solubility.
