Synthesis of Carboxamide-Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia.

We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.
PMID: 33533576 [PubMed - as supplied by publisher]

Source: ChemMedChem - February 3, 2021 Category: Chemistry Authors: Teresa Borrello M, Benelkebir H, Lee A, Hin Tam C, Shafat M, Rushworth SA, Bowles KM, Douglas L, Duriez PJ, Bailey S, Crabb SJ, Packham G, Ganesan A Tags: ChemMedChem Source Type: research