Synthesis and biological evaluation of urea derivatives as highly potent and selective rho kinase inhibitors

Journal of Medicinal Chemistry

Volumn 56, Issue 9, 2013, Pages 3568-3581

  Yin, Yan ^a,f   Lin, Li ^d   Ruiz, Claudia ^d   Khan, Susan ^d   Cameron, Michael D ^d,e   Grant, Wayne ^b   Pocas, Jennifer ^b   Eid, Nibal ^b   Park, Hajeung ^c   Schröter, Thomas ^b   Lograsso, Philip V ^b,e   Feng, Yangbo ^a  

^a Medicinal Chemistry   (United States)

^b Discovery Biology   (United States)

^c Crystallography Modeling Facility   (United States)

^d Scripps Florida   (United States)

^e SCRIPPS RESEARCH INSTITUTE   (United States)

^f SHANGHAI INSTITUTE OF TECHNOLOGY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

1[4(1H PYRAZOL 4 YLPHENYL)] 1(2 HYDROXYETHYL) 3(3 METHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 1[2(DIMETHYLAMINO) ETHYL] 3(3 METHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 1[3 (DIMETHYLAMINO) PROPYL] 3(3 METHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3 (CYCLOHEXYLMETHYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3 BENZYLUREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3 PHENETHYLUREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3 PHENYLUREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(2,3 DIMETHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(2,4 DIMETHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(2,5 DIMETHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(2,6 DIMETHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(3 FLUORO 4 METHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(3 METHOXYBENZYL) 1 METHYLUREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(3 METHOXYBENZYL) 1[2 (PYRROLIDIN 1 YL)ETHYL] UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(3 PHENYLPROPYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(3,4 DIMETHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(3,5 DIMETHOXYBENZYL) UREA; 1[4(1H PYRAZOL 4 YLPHENYL)] 3(3METHOXYBENZYL) UREA; 3[4(1H PYRAZOL 4 YLPHENYL)] 1 ETHYL 1(3 METHOXYBENZYL) UREA; 3[4(1H PYRAZOL 4 YLPHENYL)] 1 ISOPROPYL 1(3 METHOXYBENZYL) UREA; 3[4(1H PYRAZOL 4 YLPHENYL)] 1(2 HYDROXYETHYL) 1(3 METHOXYBENZYL) UREA; 3[4(1H PYRAZOL 4 YLPHENYL)] 1(3 METHOXYBENZYL) 1 METHYLUREA; ABC TRANSPORTER; BENZYL 4(1H PYRAZOL 4 YLPHENYLCARBAMATE); MOLECULAR SCAFFOLD; N [4(1H PYRAZOL 4 YLPHENYL)] 3 PHENYLPROPANAMIDE; PHENETHYL 4(1H PYRAZOL 4 YLPHENYLCARBAMATE); RHO KINASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; UREA DERIVATIVE;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DESIGN; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG METABOLISM; DRUG SCREENING; DRUG SYNTHESIS; IC 50; MAXIMUM PLASMA CONCENTRATION; MOLECULAR DOCKING; NONHUMAN; PROCESS OPTIMIZATION; PROTEIN BINDING; RAT; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; ANIMALS; CELL LINE; CHEMISTRY TECHNIQUES, SYNTHETIC; HUMANS; INHIBITORY CONCENTRATION 50; MOLECULAR DOCKING SIMULATION; PROTEIN CONFORMATION; PROTEIN KINASE INHIBITORS; RATS; RHO-ASSOCIATED KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY; UREA;

EID: 84877722667     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400062r     Document Type: Article

References (34)

1. Nakagawa, O.; Fujisawa, K.; Ishizaki, T.; Saito, Y.; Nakao, K.; Narumiya, S. ROCK-I and ROCK-II, two isoforms of Rho-associated coil-coil forming protein serine/threonine kinase in mice FEBS Lett. 1996, 392, 189-193
2. Uehata, M.; Ishizaki, T.; Satoh, H.; Ono, T.; Kawahara, T.; Morishita, T.; Tamakawa, H.; Yamagami, K.; Inui, J.; Maekawa, M.; Narumiya, S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension Nature 1997, 389, 990-994
3. Rikitake, Y.; Kim, H. H.; Huang, Z. H.; Seto, M.; Yano, K.; Asano, T.; Moskowitz, M. A.; Liao, J. K. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection Stroke 2005, 36, 2251-2257
4. Sun, H.; Breslin, J. W.; Zhu, J.; Yuan, S. Y.; Wu, M. H. Rho and ROCK signaling in VEGF-induced microvascular endothelial hyperpermeability Microcirculation 2006, 13, 237-247
5. Nakajima, E.; Nakajima, T.; Minagawa, Y.; Shearer, T. R.; Azuma, M. Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes J. Pharm. Sci. 2005, 47, 701-708
6. Ying, H.; Biroc, S. L.; Li, W.; Alicke, B.; Xuan, J. A.; Pagila, R.; Ohashi, Y.; Okada, T.; Kamata, Y.; Dinter, H. The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models Mol. Cancer Ther. 2006, 5, 2158-2164
7. Zhang, Z.; Schittenhelm, J.; Meyermann, R.; Schluesener, H. J. Lesional accumulation of RhoA(+) cells in brains of experimental autoimmune encephalomyelitis and multiple sclerosis Neuropathol. Appl. Neurobiol. 2008, 34, 231-240
8. Oka, M.; Fagan, K. A.; Jones, P. L.; McMurtry, I. F. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension Br. J. Pharmacol. 2008, 155, 444-454
9. Hu, E.; Lee, D. Rho kinase inhibitors as potential therapeutic agents for cardiovascular diseases Curr. Opin. Invest. Drugs 2003, 4, 1065-1075
10. 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, 10, 59-69
11. Liao, J. K.; Seto, M.; Noma, K. Rho kinase (ROCK) inhibitors J. Cardiovasc. Pharmacol. 2007, 50, 17-24
12. Takami, A.; Iwakubo, M.; Okada, Y.; Kawata, T.; Odai, H.; Takahashi, N.; Shindo, K.; Kimura, K.; Tagami, Y.; Miyake, M.; Fukushima, K.; Inagaki, M.; Amano, M.; Kaibuchi, K.; Iijima, H. Design and synthesis of Rho kinase inhibitors (I) Bioorg. Med. Chem. 2004, 12, 2115-2137
13. Stavenger, R.; Cui, H.; Dowdell, S.; Franz, R.; Gaitanopoulos, D.; Goodman, K.; Hilfiker, M.; Ivy, R.; Leber, J.; Marino, J.; Oh, H.; Viet, A.; Xu, W.; Ye, G.; Zhang, D.; Zhao, Y.; Jolivette, L.; Head, M.; Semus, S.; Elkins, P.; Kirkpatrick, R.; Dul, E.; Khandekar, S.; Yi, T.; Jung, D.; Wright, L.; Smith, G.; Behm, D.; Doe, C.; Bentley, R.; Chen, Z.; Hu, E.; Lee, D. Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity J. Med. Chem. 2007, 50, 2-5
14. Schirok, H.; Kast, R.; Figueroa-Pérez, S.; Bennabi, S.; Gnoth, M. J.; Feurer, A.; Heckroth, H.; Thutewohl, M.; Paulsen, H.; Knorr, A.; Hütter, J.; Lobell, M.; Münter, K.; Geiβ, V.; Ehmke, H.; Lang, D.; Radtke, M.; Mittendorf, J.; Stasch, J. P. Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors ChemMedChem 2008, 3, 1893-1904
15. Ho, K.; Beasley, J.; Belanger, L.; Black, D.; Chan, J. H.; Dumm, D.; Hu, B.; Klon, A.; Kultgen, S.; Ohlmeyer, M.; Parlato, S.; Ray, P.; Pharm, Q.; Rong, Y.; Roughton, A.; Walker, T.; Wright, J.; Xu, K.; Xu, Y.; Zhang, L.; Webb, M. Triazine and pyrimidine based ROCK inhibitors with efficacy in spontaneous hypertensive rat model Bioorg. Med. Chem. Lett. 2009, 19, 6027-6031
16. Pireddu, R.; Forinash, K. D.; Sun, N. N.; Martin, M. P.; Sung, S. S.; Alexander, B.; Zhu, J. Y.; Guida, W. C.; Schonbrunn, E.; Sebti, S. M.; Lawrence, N. J. Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2) Med. Chem. Commun. 2012, 3, 699-709
17. LoGrasso, P.; Feng, Y. Rho kinase (ROCK) inhibitors and their application to inflammatory disorders Curr. Top. Med. Chem. 2009, 9, 704-723
18. Waki, M.; Yoshida, Y.; Oka, T.; Azuma, M. Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase Curr. Eye Res. 2001, 22, 470-474
19. Tokusbige, H.; Inatani, M.; Nemoto, S.; Sakaki, H.; Katayama, K.; Uebata, M.; Tanibara, H. Effects of topical administration of Y-39983, a selective Rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys Invest. Ophthalmol. Vis. Sci. 2007, 48, 3216-3222
20. Nishio, M.; Fukunaga, T.; Sugimoto, M.; Ikesugi, K.; Sumi, K.; Hidaka, H.; Uji, Y. The effect of the H-1152p, a potent Rho-associated coiled coil-formed protein kinase inhibitor, in rabbit normal and ocular hypertensive eyes Curr. Eye Res. 2009, 34, 282-286
21. Tanihara, H.; Inatani, M.; Honjo, M.; Tokushige, H.; Azuma, J.; Araie, M. Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers Arch. Ophthalmol. 2008, 126, 309-315
22. Yin, Y.; Cameron, M.; Lin, L.; Khan, S.; Schröter, T.; Grant, W.; Pocas, J.; Chen, Y. T.; Schürer, S.; Pachori, A.; LoGrasso, P.; Feng, Y. Discovery of potent and selective urea-based ROCK inhibitors and their effects on intraocular pressure in rats ACS Med. Chem. Lett. 2010, 1, 175-179
23. Feng, Y.; Yin, Y.; Weiser, A.; Griffin, E.; Cameron, M.; Lin, L.; Ruiz, C.; Schürer, S. C.; Inoue, T.; Rao, V.; Schröter, T.; LoGrasso, P. V. Discovery of substituted 4-(pyrazol-4-yl)-phenyl-benzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors J. Med. Chem. 2008, 51, 6642-6645
24. Chen, Y. T.; Bannister, T. D.; Weiser, A.; Griffin, E.; Lin, L.; Ruiz, C.; Cameron, M.; Schürer, S.; Duckett, D.; Schröter, T.; LoGrasso, P. V.; Feng, Y. Chroman-3-amides as potent Rho kinase inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 6406-6409
25. Sessions, E. H.; Yin, Y.; Bannister, T. D.; Weiser, A.; Griffin, E.; Pocas, J.; Cameron, M.; Ruiz, C.; Lin, L.; Schürer, S. C.; Schröter, T.; LoGrasso, P. V.; Feng, Y. Benzimidazole-and benzoxazole-based inhibitors of Rho kinase Bioorg. Med. Chem. Lett. 2008, 18, 6390-6393
26. Yin, Y.; Lin, L.; Ruiz, C.; Cameron, M.; Pocas, J.; Grant, W.; Schröter, T.; Chen, W.; Duckett, D.; Schürer, S.; LoGrasso, P. V.; Feng, Y. Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 6686-6690
27. Fang, X.; Yin, Y.; Chen, Y. T.; Yao, L.; Wang, B.; Cameron, M.; Lin, L.; Khan, S.; Ruiz, C.; Schröter, T.; Grant, W.; Weiser, A.; Pocas, J.; Pachori, A.; Schürer, S.; LoGrasso, P.; Feng, Y. Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors J. Med. Chem. 2010, 53, 5727-5737
28. Chowdhury, S.; Sessions, E. H.; Pocas, J. R.; Grant, W.; Schröter, T.; Lin, L.; Ruiz, C.; Cameron, M. D.; Schuerer, S.; LoGrasso, P. V.; Bannister, T. D.; Feng, Y. Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I) Bioorg. Med. Chem. Lett. 2011, 21, 7107-7112
29. Sessions, E. H.; Chowdhury, S.; Yin, Y.; Pocas, J. R.; Grant, W.; Schroeter, T.; Lin, L.; Ruiz, C.; Cameron, M. D.; LoGrasso, P. V.; Bannister, T. D.; Feng, Y. Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-II) Bioorg. Med. Chem. Lett. 2011, 21, 7113-7118
30. Fang, X.; Chen, Y. T.; Sessions, E. H.; Chowdhury, S.; Vojkovsky, T.; Yin, Y.; Pocas, J. R.; Grant, W.; Schröter, T.; Lin, L.; Ruiz, C.; Cameron, M. D.; LoGrasso, P. V.; Bannister, T. D.; Feng, Y. Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 1844-1848
31. Chowdhury, S.; Chen, Y. T.; Fang, X.; Grant, W.; Pocas, J. R.; Cameron, M. D.; Ruiz, C.; Lin, L.; Park, H.; Schröter, T.; Bannister, T. D.; LoGrasso, P. V.; Feng, Y. Rock-II Inhibitors Based on Amino Acid Derived Qinazolines Bioorg. Med. Chem. Lett. 2013, 23, 1592-1599
32. Schröter, T.; Griffin, E.; Weiser, A.; Feng, Y.; LoGrasso, P. Detection of myosin light chain phosphorylation-A cell-based assay for screening Rho-kinase inhibitors Biochem. Biophys. Res. Commun. 2008, 374, 356-360
33. Schröter, T.; Minond, D.; Weiser, A.; Dao, C.; Habel, J.; Spicer, T.; Chase, P.; Baillargeon, P.; Scampavia, L.; Schürer, S.; Chung, C.; Mader, C.; Southern, M.; Tsinoremas, N.; LoGrasso, P.; Hodder, P. Comparison of miniaturized time-resolved fluorescence resonance energy transfer and enzyme-coupled luciferase high-throughput screening assays to discovery inhibitors of Rho-kinase II (ROCK-II) J. Biomol. Screen. 2008, 13, 17-28
34. Vaasa, A.; Viil, I.; Enkvist, E.; Viht, K.; Raidaru, G.; Lavogina, D.; Uri, A. High-affinity bisubstrate probe for fluorescence anisotropy binding/displacement assays with protein kinases PKA and ROCK Anal. Biochem. 2009, 385, 85-93