Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase Inhibitors

Abstract

Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC(50) = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.

Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

“…41, 53 Thus, compound 18w was applied to the right eyes of an elevated IOP rat model (initial IOP was ~ 28 mmHg) using a dose of 50 μg (20 μL drop of a 0.25% solution). As shown in Figure 7, significant decreases in IOP were detected at 4 h, slightly weakened at 7 h, and IOP returning to baseline at 24 h as compared to the vehicle.…”

Statins and Selective Inhibition of Rho Kinase Protect Small Conductance Calcium-Activated Potassium Channel Function (KCa2.3) in Cerebral Arteries

“…The residual hyperpolarization was abolished by the additional presence of apamin (0.2±1.8 mV, n = 4, P<0.05; Figure 3D, E). A structurally distinct and extremely selective Rho kinase inhibitor SR5037 [20] had a similar effects to Y27632. This novel agent reversed vasoconstriction to L-NAME (relaxation of 85.2±3.7% n = 4) and the remaining tension was too small to assess accurately.…”

“…We have previously reported that under these conditions only K Ca 3.1 contribute to EDH [1] thus the other K Ca channel blockers were added in the sequence detailed above only if the previous K Ca blocker(s) failed to prevent hyperpolarization. K Ca channel blockers were assessed against EDH responses to SLIGRL (20 µM) in the presence of: 1. the Rho kinase inhibitors Y27632 (10 µM) [19] or SR5037 (1 µM) [20] as no kinase inhibitor is 100% selective we chose two structurally distinct inhibitors at concentrations approximately 100 times their respective Ki/IC 50 for Rho kinase to ensure full inhibition with minimal effects on other, related kinases [19], [20]; 2. the HMG-CoA inhibitors simvastatin (0.1 and 1 µM) or lovastatin (100 nM).These concentrations of statins are similar to the concentrations found in human plasma (circa 25–90 nM) [21] and are in line with their K i values of low to high nanomolar, reported in various rat cell types [22] In some experiments, in the presence of L-NAME and simvastatin (100 nM) the vessels were also incubated with the isoprenoid geranylgeranyl-pyrophosphate (GGPP, 1 µM). The concentration of GGPP used corresponds to those reported to reverse statin mediated inhibition of RhoA in vascular endothelial cells [15], [23] Papaverine (150 µM) was added at the end of each experiment to assess overall tone (previous experiments show this was sufficient to give a maximal relaxation indistinguishable from that obtained in the presence of zero calcium [24].…”

Palladium-catalyzed double carbonylation-based diversity-oriented synthesis of 3,4-dihydroisoquinoline-1-carboxamides

“…Phenethylamine derivative 1c is synthesized from the amine 4. 14 Compound 1d is prepared by transforming 2-iodobenzylbromide (5). Alkylation of 5 with ethyl malonate and subsequent decarboxylation affords 6 in a good yield.…”

“…1, red color) structural motif can be found in bioactive compounds such as peroxisome proliferatoractivated receptor d (PPAR d) agonist, 2 opioid antagonist, 3 farnesyl transferase inhibitor, 3a,4 and Rho kinase II (ROCK-II) selective inhibitor. 5 Since the THIQ-1-carboxamides can be construed as conformationally constrained analogues of phenyl alanine (tyrosine) or a surrogate of proline, they are often used as building blocks in the synthesis of modified peptides.…”