SAR-407899

SAR-407899 is a potent and selective Rho kinase inhibitor with promising antihypertensive activity. SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries. SAR407899 is equipotent against human and rat-derived Rho-kinase 2 with inhibition constant values of 36 nM and 41 nM, respectively. SAR407899 is approximately 8-fold more active than fasudil. SAR407899 potently (mean IC(50) values: 122 to 280 nM) and species-independently relaxed precontracted isolated arteries of different species and different vascular beds. The antihypertensive effect of SAR407899 was superior to that of fasudil and Y-27632.

Product information

CAS Number: 923359-38-0

Molecular Weight: 244.29

Formula: C14H16N2O2

Synonym:

SAR407899

SAR 407899

SAR-407899

SAR407899 HCl

Related CAS Number:

923262-96-8 (HCl)

Chemical Name: 6-(piperidin-4-yloxy)isoquinolin-1(2H)-one

Smiles: O=C1NC=CC2=CC(=CC=C21)OC1CCNCC1

InChiKey: IPEXHQGMTHOKQV-UHFFFAOYSA-N

InChi: InChI=1S/C14H16N2O2/c17-14-13-2-1-12(9-10(13)3-8-16-14)18-11-4-6-15-7-5-11/h1-3,8-9,11,15H,4-7H2,(H,16,17)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

SAR407899 is a potent and ATP-competitive ROCK inhibitor, with Kis of 36 nM and 41 nM for human and rat ROCK-2, respectively. SAR407899 inhibits ROCK-2 better than ROCK-1, with IC50s of 102 ± 19 nM and 276 ± 26 nM, respectively, in the presence of 40 μM ATP. SAR407899 also less potently inhibits PKC-Δ and MSK-1, with IC50s of 5.4 and 3.1 μM, respectively. SAR407899 (0.1, 0.3, 1.0, and 3.0 μM) specifically inhibits the ROCK-mediated phosphorylation of MYPTT696 in HeLa cells stimulated with PHEN, and shows such effects at 1 μM and 10 μM in primary rat aortic smooth muscle cells. SAR407899 (3 μM) completely blocks thrombin-induced shrinkage of human umbilical vein endothelial cells (HUVECs) and stress fiber formation. SAR407899 concentration-dependently inhibits 5-bromodeoxyuridine incorporation into the cells with an IC50 of 5.0 ± 1.3 μM. SAR407899 also effectively inhibits THP-1 migration with an IC50 of 2.5 ± 1.0 μM. SAR407899 shows a potent vasorelaxant activity in a broad variety of isolated arteries taken from different vascular beds and species, with a range of IC50 values between 122 and 280 nM. SAR407899 dose-dependently relaxes the phenylephrine pre-contracted smooth muscle, with IC50s of 0.07 and 0.05 μM, respectively.

In Vivo:

SAR407899 (3 mg/kg, i.v.) inhibits ROCK-mediated phosphorylation of MYPTT696 in thoracic aorta of spontaneously hypertensive rats (SHRs). SAR407899 (0.01-0.30 mg/kg, i.v.) efficiently reduces pressor responses to vasoconstrictor agents in rats. SAR407899 (1, 3, 10, and 30 mg/kg, p.o.) dose dependently lowers blood pressure in hypertensive SHRs[1]. SAR407899 (1-3 mg/kg, i.v. or 3, 10 mg/kg, p.o.) increases the length of the penis in healthy rabbits. SAR407899 (3-10 mg/kg, p.o.) also dose-dependently increases penile length in diabetic rabbits.

References:

1. Lohn M, Plettenburg O, Kannt A, Kohlmann M, Hofmeister A, Kadereit D, Monecke P, Schiffer A, Schulte A, Ruetten H, Ivashchenko Y. End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899. World J Cardiol. 2015 Jan 26;7(1):31-42. doi: 10.4330/wjc.v7.i1.31. PubMed PMID: 25632317; PubMed Central PMCID: PMC4306204.
2. Babelova A, Jansen F, Sander K, Löhn M, Schäfer L, Fork C, Ruetten H, Plettenburg O, Stark H, Daniel C, Amann K, Pavenstädt H, Jung O, Brandes RP. Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease. PLoS One. 2013 Nov 7;8(11):e80328. doi: 10.1371/journal.pone.0080328. eCollection 2013. PubMed PMID: 24244677; PubMed Central PMCID: PMC3820652.
3. Guagnini F, Ferazzini M, Grasso M, Blanco S, Croci T. Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa. J Transl Med. 2012 Mar 23;10:59. doi: 10.1186/1479-5876-10-59. PubMed PMID: 22444253; PubMed Central PMCID: PMC3328245.
4. Grisk O, Schlüter T, Reimer N, Zimmermann U, Katsari E, Plettenburg O, Löhn M, Wollert HG, Rettig R. The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries. J Hypertens. 2012 May;30(5):980-9. doi: 10.1097/HJH.0b013e328351d459. PubMed PMID: 22388233.
5. Löhn M, Plettenburg O, Ivashchenko Y, Kannt A, Hofmeister A, Kadereit D, Schaefer M, Linz W, Kohlmann M, Herbert JM, Janiak P, O'Connor SE, Ruetten H. Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension. 2009 Sep;54(3):676-83. doi: 10.1161/HYPERTENSIONAHA.109.134353. Epub 2009 Jul 13. PubMed PMID: 19597037.

Products are for research use only. Not for human use.