3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors

ROCK inhibitors in ocular disease

“…Then we must consider the best and most feasible method of drug administration. Because of the short biological half-life [2,7,100] of ROCK inhibitors, repeated applications of intravitreal injections or eye drops will be necessary. Intravitreal implantation of a slowly releasing drug delivery system may offer an doi: 10.5599/admet.4.4.331 297 alternative solution.…”

“…For example, the fasudil derivative ripasudil at 50 % of its effective concentration against ROCK I in cell free assays (IC50(Ki)=0.051 µM) [6] has at least a 2-6 times higher binding affinity than that of other ROCK inhibitors such as Y27632 (IC 50(Ki) =0.14 µM) or fasudil (IC 50(Ki) =0.33 µM) [5] at the same effective concentration. AMA0076 and Y39983 are both structurally related to Y27632 [7]. In in vitro assays, AMA0076 (IC50=2.3+/-0.9 nM) and Y39983 (IC50=4.3+/-2.1 nM) showed similar on-target potency for ROCK II, but they were at least ten times more potent than Y27632 (IC50=54+/-23 nM).…”

“…AMA0076, designed by Amakem, is called a soft ROCK inhibitor (see definition in introduction), because its effects are localized thereby resulting in fewer side effects. The compound contains a carboxylic ester group and exhibits high ROCK efficacy (ROCK II IC50=2.5 nM) [7]. Topically instilled drug, once it gets through the cornea into the aqueous humor, remains stable.…”

“…These drugs are known as soft drugs. Adding (and modifying) ester moieties to an otherwise classical ROCK inhibitor results in variability in drug stability, with plasma half-life times from less than 5 minutes to more than 120 minutes [7]. AMA0076 lowered intraocular pressure in New Zealand white rabbits with minimal hyperemia, and was more efficient than Y39983 at the same concentration [8].…”

Design, synthesis and biological characterization of selective LIMK inhibitors

“…The latter was attempted with the purpose of optimizing interactions with residues located around the Glycine-rich loop or beyond, which are not conserved between LIMKs and ROCKs. Ester chains were favored in our design, as they left open the possibility of a soft drug approach for avoiding ROCK-associated side effects, 20 in case the ROCK activity observed with LX-7101 could not be eliminated.…”