- Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors
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RhoA and its downstream effector ROCK mediate stress fiber formation and cell contraction through their effects on the phosphorylation of myosin light chain (MLC). Inhibition of the RhoA/ROCK pathway has proven to be a promising strategy for several indications such as cardiovascular disease, glaucoma, and inflammatory disease. In 2010, our group reported urea-based ROCK inhibitors as potential antiglaucoma agents. These compounds showed potent IC50 values in enzymatic and cell-based assays and significant intraocular pressure (IOP)-lowering effects in rats (~7 mmHg).(22) To develop more advanced ROCK inhibitors targeting various potential applications (such as myocardial infarction, erectile dysfunction, multiple sclerosis, etc.) in addition to glaucoma, a thorough SAR for this urea-based scaffold was studied. The detailed optimization process, counter-screening, and in vitro and in vivo DMPK studies are discussed. Potent and selective ROCK inhibitors with various in vivo pharmacokinetic properties were discovered.
- Yin, Yan,Lin, Li,Ruiz, Claudia,Khan, Susan,Cameron, Michael D.,Grant, Wayne,Pocas, Jennifer,Eid, Nibal,Park, Hajeung,Schr?ter, Thomas,Lograsso, Philip V.,Feng, Yangbo
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p. 3568 - 3581
(2013/06/27)
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- Pyrano-[2,3b]-pyridines as potassium channel antagonists
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The design and synthesis of a series of highly functionalized pyrano-[2,3b]-pyridines is described. These compounds were assayed for their ability to block the IKur channel encoded by the gene hKV1.5 in patch-clamped L-929 cells. Six of the compounds in this series showed sub-micromolar activity, the most potent being 4-(4-ethyl-benzenesulfonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3b]-pyridine-6-carboxylic acid ethyl-phenyl-amide with an IC50 of 378 nM.
- Finlay, Heather J.,Lloyd, John,Nyman, Michael,Conder, Mary Lee,West, Tonya,Levesque, Paul,Atwal, Karnail
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p. 2714 - 2718
(2008/12/21)
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- Central cholinergic agents. I. Potent acetylcholinesterase inhibitors, 2-[ω-[N-alkyl-N-(ω-phenylalkyl)amino]alkyl]-1H-isoindole-1,3(2H)-dion es, based on a new hypothesis of the enzyme's active site
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It has been suggested that the active site of acetylcholinesterase contains a hydrophobic binding site (HBS-1), which is closely adjacent to both the anionic and the esteratic sites. In this paper, we assumed that there exists another hydrophobic binding site (HBS-2), some distance removed from the anionic site. On this assumption, a new working hypothesis was proposed for the design of acetylcholinesterase inhibitors. A series of 2-[ω-[N-alkyl-N-(ω-phenylalkyl)amino]alkyl]-1H-isoindole-1,3(2H)-dion es was designed based on this hypothesis and tested for its inhibitory activities on acetylcholinesterase. Some in this series were revealed to be more potent than physostigmine. Optimum activity was found to be associated with a five carbon chain length separating the benzylamino group from the 1H-isoindole-1,3(2H)-dione (phthalimide) moiety. Quantitative study of substitution effect on the phthalimide moiety revealed that hydrophilic and electron-withdrawing groups enhance the activity.
- Ishihara,Kato,Goto
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p. 3225 - 3235
(2007/10/02)
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