Rho-kinase Inhibitors: Pharmacomodulations on the Lead Compound Y-32885

Abstract

In order to specify structure-activity relationships we have synthesized new series of analogues of the Rho-kinase inhibitor (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide (Y-32885). The structural modifications concerned the 1-aminoethyl, the pyridyl and the amide groups which are the main features of this lead compound. Our analogue derivatives were evaluated on GTPgammaS-induced contraction in permeabilized smooth-muscle and on the actin cytoskeleton. All the modifications result in a diminution or a loss of activity showing that interactions of Y-32885 with the catalytic domain of Rho-kinase seem to be particularly definite and sensitive to structural variations. The presence of a pyridine moiety and a basic amine group separated by a spacer bearing an amide function are of utmost importance.

Identifying novel targets in renal cell carcinoma: Design and synthesis of affinity chromatography reagents

“…Condensation of the protected benzoic acid 25 20 with 3-aminopyridine gave the amide 26 which was deprotected and coupled to 4-iodophenylsulfonyl chloride to give the iodide 28 (Scheme 4). Sonogashira coupling was used to attach long chain linkers to the PPB core structure.…”

“…Oxalyl chloride (4.58 mL, 52.5 mmol) was added dropwise to a solution of 4-(benzyloxycarbonylamino)methyl)benzoic acid 25 20 (10.0 g, 35.0 mmol) and DMF (4 drops) in dry THF (150 mL), and the mixture stirred at 50 °C for 4 h. The solvent was evaporated and the residue dissolved in pyridine (80 mL). 3-Aminopyridine (3.62 g, 38.5 mmol) was added and the solution stirred at 20 °C for 48 h. Water (150 mL) was added, the mixture stirred for another 2 h, the precipitate filtered off, washed with water and dried to give the carbamate 26 (7.82 g, 62%) as a white solid: mp (EtOH) 207–210 °C; 1 H NMR δ 10.37 (s, 1H, NHCO), 8.92 (d, J = 2.3 Hz, 1H, H-2′), 8.31 (dd, J = 4.7, 1.5 Hz, 1H, H-6′), 8.18 (ddd, J = 8.3, 2.5, 1.5 Hz, 1H, H-4′), 7.93 (br d, J = 8.3 Hz, 2H, H-2, H-6), 7.89 (br t, J = 6.0 Hz, 1H, NHCO 2 ), 7.41 (br d, J = 8.3 Hz, 2H, H-3, H-5), 7.31–7.39 (m, 6 H, H-5′, H-2″, H-3″, H-4″, H-5″, H-6″), 5.06 (s, 2H, CH 2 O), 4.30 (d, J = 6.2 Hz, 2H, CH 2 N).…”

“…Oxalyl chloride (0.92 mL, 10.5 mmol) was added dropwise to a stirred suspension of benzoic acid 25 20 (2.0 g, 7.0 mmol) and DMF (3 drops) in dry THF (50 mL) and the solution was stirred at 20 °C for 4 h. The solvent was evaporated and the residue dissolved in pyridine (10 mL). Aniline (0.70 mL, 7.7 mmol) was added and the solution stirred at 20 °C for 16 h. The solvent was evaporated and the residue suspended in ice/water (100 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried to give crude benzyl 4-(anilinocarbonyl)benzyl carbamate ( 33 ) (1.45 g, 57%) as a white powder: mp (H 2 O) 276–279 °C; 1 H NMR δ 10.16 (s, 1H, CONH), 7.86–7.93 (m, 3H, NHCO 2 , H aryl ), 7.77 (d, J = 8.6 Hz, 2H, H aryl ), 7.30–7.41 (m, 9H, H aryl ), 7.10 (br t, J = 7.3 Hz, 1H aryl ), 4.14 (br q, J = 5.4 Hz, 2H, CH 2 N).…”

New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling

“…The Rho kinase inhibitors include the pyridine derivative Y-27632,29 the closely related compound Y-3288530 and fasudil with its derivatives: HA-1077 and H-1152 31 32. Y-27632 was originally developed as a smooth muscle relaxant and was shown to inhibit stress fibre formation in fibroblasts, endothelial contraction and thrombin induced DNA synthesis in rat aortic smooth muscle cells (SMC) 33…”

A structural study of the complex between neuroepithelial cell transforming gene 1 (Net1) and RhoA reveals a potential anticancer drug hot spot

“…The dysregulation of Rho proteins contributes to tumorigenesis, metastasis (3), hypertension (4,5), diabetes (6,7), inflammation (8), neuroplasticity (9), and cancer (3). Thus, targeting Rho GTPase signaling pathways has emerged as a promising therapeutic strategy (10,11).…”