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Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.

Green J, Cao J, Bandarage UK, Gao H, Court J, Marhefka C, Jacobs M, Taslimi P, Newsome D, Nakayama T, Shah S, Rodems S
J Med Chem 58 5028-37 (2015)
Related entries: 2erz, 2esm, 2etk, 2etr, 3d9v, 4yvc, 5bml, 5hvu

Cited: 11 times
EuropePMC logo PMID: 26039570

Abstract

The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.

Reviews citing this publication (2)

  1. Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities. Chin VT, Nagrial AM, Chou A, Biankin AV, Gill AJ, Timpson P, Pajic M. Expert Rev Mol Med 17 e17 (2015)
  2. Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity. Laczi D, Johnstone MD, Fleming CL. Chem Asian J 17 e202200200 (2022)

Articles citing this publication (9)

  1. Rho-Kinase inhibitor fasudil suppresses high glucose-induced H9c2 cell apoptosis through activation of autophagy. Gao H, Hou F, Dong R, Wang Z, Zhao C, Tang W, Wu Y. Cardiovasc Ther 34 352-359 (2016)
  2. A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease. McKerracher L, Shenkar R, Abbinanti M, Cao Y, Peiper A, Liao JK, Lightle R, Moore T, Hobson N, Gallione C, Ruschel J, Koskimäki J, Girard R, Rosen K, Marchuk DA, Awad IA. Transl Stroke Res 11 365-376 (2020)
  3. Auto In Silico Ligand Directing Evolution to Facilitate the Rapid and Efficient Discovery of Drug Lead. Wu F, Zhuo L, Wang F, Huang W, Hao G, Yang G. iScience 23 101179 (2020)
  4. Rho-associated coiled-coil kinase 1 activation mediates amyloid precursor protein site-specific Ser655 phosphorylation and triggers amyloid pathology. Hu YB, Ren RJ, Zhang YF, Huang Y, Cui HL, Ma C, Qiu WY, Wang H, Cui PJ, Chen HZ, Wang G. Aging Cell 18 e13001 (2019)
  5. IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models. Gasilina A, Premnauth G, Gurjar P, Biesiada J, Hegde S, Milewski D, Ma G, Kalin TV, Merino E, Meller J, Seibel W, Cancelas JA, Vinnedge LP, Nassar NN. PLoS One 15 e0229801 (2020)
  6. Identification of Novel Rho-Kinase-II Inhibitors with Vasodilatory Activity. Kesar S, Paliwal S, Mishra P, Madan K, Chauhan M, Chauhan N, Verma K, Sharma S. ACS Med Chem Lett 11 1694-1703 (2020)
  7. Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis. Ouvry G, Atrux-Tallau N, Bihl F, Bondu A, Bouix-Peter C, Carlavan I, Christin O, Cuadrado MJ, Defoin-Platel C, Deret S, Duvert D, Feret C, Forissier M, Fournier JF, Froude D, Hacini-Rachinel F, Harris CS, Hervouet C, Huguet H, Lafitte G, Luzy AP, Musicki B, Orfila D, Ozello B, Pascau C, Pascau J, Parnet V, Peluchon G, Pierre R, Piwnica D, Raffin C, Rossio P, Spiesse D, Taquet N, Thoreau E, Vatinel R, Vial E, Hennequin LF. ChemMedChem 13 321-337 (2018)
  8. Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal-regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment. Zaky YA, Rashad MW, Zaater MA, El Kerdawy AM. BMC Chem 18 2 (2024)
  9. The Design, Synthesis and Evaluation of Rho-kinase Inhibitory Activity of 4-aryl-thiazole-2-amines. Wang L, Ouyang B, Fan M, Qi J, Yao L. Iran J Pharm Res 20 121-131 (2021)


Related citations provided by authors (2)

  1. The structure of dimeric ROCK I reveals the mechanism for ligand selectivity.. Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J J Biol Chem 281 260-8 (2006)
  2. ROCK inhibitors 2. Improving potency, selectivity and solubility through the application of rationally designed solubilizing groups.. Gao H, Marhefka C, Jacobs MD, Cao J, Bandarage UK, Green J Bioorg Med Chem Lett 28 2616-2621 (2018)

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