84468-24-6Relevant articles and documents
Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis
Martín-Cámara, Olmo,Arribas, Marina,Wells, Geoffrey,Morales-Tenorio, Marcos,Martín-Requero, ángeles,Porras, Gracia,Martínez, Ana,Giorgi, Giorgio,López-Alvarado, Pilar,Lastres-Becker, Isabel,Menéndez, J. Carlos
, p. 1867 - 1882 (2022/01/20)
Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.
Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B
Collins, Ian,Caldwell, John,Fonseca, Tatiana,Donald, Alastair,Bavetsias, Vassilios,Hunter, Lisa-Jane K.,Garrett, Michelle D.,Rowlands, Martin G.,Aherne, G. Wynne,Davies, Thomas G.,Berdini, Valerio,Woodhead, Steven J.,Davis, Deborah,Seavers, Lisa C. A.,Wyatt, Paul G.,Workman, Paul,McDonald, Edward
, p. 1255 - 1273 (2007/10/03)
Structure-based drug design of novel isoquinoline-5-sulfonamide inhibitors of PKB as potential antitumour agents was investigated. Constrained pyrrolidine analogues that mimicked the bound conformation of linear prototypes were identified and investigated by co-crystal structure determinations with the related protein PKA. Detailed variation in the binding modes between inhibitors with similar overall conformations was observed. Potent PKB inhibitors from this series inhibited GSK3β phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells.
Isoquinolinesulfonyl derivatives and process for the preparation thereof
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, (2008/06/13)
A 5-isoquinolinesulfonyl derivative of Formula (I): STR1 wherein l is zero or one; m and n each is an integer of one to nine; m+n is an integer of at least one; R1 is a hydrogen atom, a C1-10 alkyl group, a C5-6 cycloalkyl group or an aryl group; or R2 and R3 each is a hydrogen atom, a C1-10 alkyl group, a C5-6 cycloalkyl group, an aryl group or an aralkyl group; R2 and R3 are C1-6 alkylene groups and linked directly or through an oxygen atom to form a 5- to 7-membered heterocyclic ring with the adjacent nitrogen atom; or the STR2 group is a STR3 group wherein R4 and R5 each is a hydrogen atom, a C1-10 alkyl group, an aryl group or an aralkyl group and R6 is a hydrogen atom, a C1-10 alkyl group, and aryl group, an aralkyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group or a STR4 group wherein R7 is a C1-8 alkyl group; and the pharmaceutically acceptable salt thereof; and a process for the preparation thereof. The compounds of this invention have a relaxatory action for vascular smooth muscle and are useful as a vasodilator and a hypotensor.
