Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks

Glycogen synthase kinase-3β (GSK3β) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3β/p38α mitogen-activated protein kinase inhibitors and identified N-(4-(4-(4-fluorophenyl)-2-methyl-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (1) as a potent dual inhibitor of both target kinases. In this study, we aimed to design selective GSK3β inhibitors based on our pyridinylimidazole scaffold. Our efforts resulted in several novel and potent GSK3β inhibitors with IC50 values in the low nanomolar range. 5-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (6g) displayed very good kinase selectivity as well as metabolical stability and inhibited GSK3β activity in neuronal SH-SY5Y cells. Interestingly, we observed the importance of the 2-methylimidazole's tautomeric state for the compound activity. Finally, we reveal how this crucial tautomerism effect is surmounted by imidazole-2-carboxamides, which are able to stabilize the binding via enhanced water network interactions, regardless of their tautomeric state

Discovery and evaluation of enantiopure 9H-pyrimido[4,5\u2010b]indoles as nanomolar GSK\u20103\u3b2 inhibitors with improved metabolic stability

Glycogen synthase kinase\u20103\u3b2 (GSK\u20103\u3b2) is a potential target in the field of Alzheimer\u2019s disease drug discovery. We recently reported a new class of 9H\u2010pyrimido[4,5\u2010b]indole\u2010based GSK\u2010 3\u3b2 inhibitors, of which 3\u2010(3\u2010((7\u2010chloro\u20109H\u2010pyrimido[4,5\u2010b]indol\u20104\u2010yl)(methyl)amino)piperidin\u20101\u2010yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide\u2010based derivatives and studied their structure\u2013activity relationships against GSK\u20103\u3b2 supported by 1 \u3bcs molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)\u20103\u2010(3\u2010((7\u2010chloro\u20109H\u2010pyrimido[4,5\u2010b]indol\u20104\u2010 yl)(methyl)amino)piperidin\u20101\u2010yl)\u20103\u2010oxopropanenitrile ((R)\u20102) and (R)\u20101\u2010(3\u2010((7\u2010bromo\u2010 9Hpyrimido[4,5\u2010b]indol\u20104\u2010yl)(methyl)amino)piperidin\u20101\u2010yl)propan\u20101\u2010one ((R)\u201028), exhibited IC50 values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties