RGNCY-0061 (CM-414 HDAc and PDE5 inhibitor)
CM-414 is a first-in-class small molecule that acts as a dual inhibitor of PDE5 and HDACs. The targeting of two independent but synergistic activities of HDACs (histone deacetylase clas I and HDAC6) and PDE5 (phosphodiesterase 5) has recently been validated as a potentially novel approach for Alzheimer's disease therapy. CM-414 was used as a probe to validate this therapeutic target and demonstrated that an increase in activiation of cAMP/cGMP responsive element binding protein (CREB) induced by PDE5 inhibition combined with HDAC class I inhibition resulted in efficient histone acetylation. CM-414 rescued the impaired long term potentiation evident in hippocampal slices from APP/PS1 mice. In addition,the chronic treatment f Tg2576 mice with CM-414 diminished brain Aβ and pTau levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons and reversed their cognitive deficits. CM-414 presents a unique and exciting strategy in the treatment of Alzhemier's disease.
Systematic Name: 3-(4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl)-N-hydroxycyclobutane-1-carboxamide
Mol Wt: 439.52
Tags: Alzheimer’s, Alzheimers, small molecule, CM-414, RGNCY-0061, PDE5, HDAC, HDACs