911417-87-3

KD 025 is an inhibitor of Rho-associated kinase 2 (ROCK2; IC₅₀ = 0.105 μM). It is selective for ROCK2 over ROCK1 (IC₅₀ = 24 μM). KD 025 (10 μM) decreases the expression of connective tissue growth factor (CTGF) and induces remodeling of the actin cytoskeleton in isolated human ileal fibrotic smooth muscle cells. It inhibits heat-killed C. albicans- or S. epidermidis-induced production of IL-17 in isolated human peripheral blood mononuclear cells (PBMCs) when used at concentrations ranging from 1.25 to 10 μM. KD 025 (100 and 200 mg/kg) reduces infarct volume in a mouse model of cerebral ischemia induced by transient middle cerebral artery occlusion (MCAO). It decreases disease severity in a mouse model of sclerodermatous chronic graft versus host disease (GVHD) when administered at a dose of 150 mg/kg. Formulations containing KD 025 have been used in the treatment of chronic GVHD.

KD 025 is an inhibitor of Rho-associated protein kinase II (ROCK-II), a serine/threonine kinase that regulates the formation of actin stress fibers and focal adhesions, smooth muscle contraction, and gene expression (1, 2). KD025 has been shown to reduce infarct volume after transient middle cerebral artery occlusion (2).

Belumosudil is an orally active drug approved for the treatment of chronic graft-versus-host disease (cGVHD). cGVHD is a chronic inflammatory disease that occurs in patients who have undergone allogeneic haematopoietic cell transplantation (allo-HCT), resulting in long-term multi-organ complications.

Rezurock

Class: serine-threonine kinase; Treatment: chronic GVHD; Other name: SLx-2119, KD025; Oral bioavailability = 64%; Elimination half-life = 19 h; Protein binding = 99.9%

Belumosudil is a Rho-associated coiled-coil-containing protein kinase-2 (ROCK2) inhibitor. Inhibition of ROCK2 reduces cytokine production through down-regulation of signal transduction and activation of phosphorylation of transcription factor 3 (STAT3). In addition, Belumosudil promotes the production of regulatory T cells by upregulating the phosphorylation of STAT5. These effects contribute to the reduction of symptoms in patients with cGVHD.

Belumosudil was synthesised as follows: bromoacetyl bromide (17.1) was reacted with isopropylamine (17.2) to form amide 17.3. Subsequent bromine substitution using methyl 3-hydroxybenzoate (17.4) formed ether 17.5. Saponification of the ester yielded carboxylic acid 17.6, which was converted to a chloroform using oxalyl chloride, and was subsequently reacted with 2-amino benzamide ( 17.7) to form amide 17.8. the ring was buckled under strong alkaline conditions to form quinazolinone 17.9, which was then chlorinated to 4-chloroquinazoline 17.10 using sulfoxide chloride. the final reaction was a direct SNAr reaction using 5-aminoindolazole (17.11), which completed the synthesis of belumosidul. the synthesis of belumosudil was completed using oxalyl chloride to convert the carboxylic acid 17.6 to a chloride. The final step of converting belumosudil to methanesulfonate is not described in the patent, but may have been achieved by treatment with methanesulfonic acid 17.

Primary target: ROCK2

Boerma et al. (2008) Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin; Blood Coagul. Fibrinolysis.?19 709 Zanin-Zhorov et al. (2014) Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism; Natl. Acad. Sci. USA?111 16814 Flynn et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism; 127 2144 Jagasia et al. (2021) ROCK2 Inhibition with Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease; Clin. Invest.?39 1888 Diep et al. (2018) Anti-adipogenic effects of KD025 (SLx-2119), a ROCK2-specific inhibitor, in 3T3-L1 cells; Rep.?8 2477 Diep et al. (2019) KD025 (SLx-2119) suppresses adipogenesis at intermediate stage in human adipose-derived stem cells; Adipocyte?9 114 Wei et al. (2020) ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice; FASEB J.?34 474 Tran and Chun (2021) ROCK2-Specific Inhibitor KD025 Suppresses Adipocyte Differentiation by Inhibiting Casein Kinase 2; Molecules?26 4747