Discovery of aminofurazan-azabenzimidazoles as inhibitors of rho-kinase with high kinase selectivity and antihypertensive activity

Journal of Medicinal Chemistry

Volumn 50, Issue 1, 2007, Pages 2-5

  Stavenger, Robert A ^a   Cui, Haifeng ^a   Dowdell, Sarah E ^a   Franz, Robert G ^a   Gaitanopoulos, Dimitri E ^a   Goodman, Krista B ^a   Hilfiker, Mark A ^a   Ivy, Robert L ^a   Leber, Jack D ^a   Marino Jr , Joseph P ^a   Oh, Hye Ja ^a   Viet, Andrew Q ^a   Xu, Weiwei ^a   Ye, Guosen ^a   Zhang, Daohua ^a   Zhao, Yongdong ^a   Jolivette, Larry J ^a   Head, Martha S ^b   Semus, Simon F ^b   Elkins, Patricia A ^b   Kirkpatrick, Robert B ^b   Dul, Edward ^b   Khandekar, Sanjay S ^b   Yi, Tracey ^b   Jung, David K ^b   Wright, Lois L ^b   Smith, Gary K ^b   Behm, David J ^a   Doe, Christopher P ^a   Bentley, Ross ^a   Chen, Zunxuan X ^a   Hu, Erding ^a   Lee, Dennis ^a   more..

^a CVU CEDD ^*  (United States)

^b GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AZABENZIMIDAZOLE; FASUDIL; FURAZAN DERIVATIVE; IMIDAZOLE DERIVATIVE; MORPHOLINE DERIVATIVE; RHO ASSOCIATED KINASE 1; RHO KINASE; RHO KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; DISEASE MODEL; DISTRIBUTION VOLUME; DRUG BINDING; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME ACTIVITY; ENZYME INHIBITION; HYPERTENSION; IC 50; NONHUMAN; RAT; STRUCTURE ANALYSIS;

ANIMALS; ANTIHYPERTENSIVE AGENTS; AORTA; BENZIMIDAZOLES; BLOOD PRESSURE; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MODELS, MOLECULAR; MUSCLE CONTRACTION; MUSCLE, SMOOTH, VASCULAR; OXADIAZOLES; PROTEIN-SERINE-THREONINE KINASES; RATS; RATS, INBRED SHR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33846246321     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060873p     Document Type: Article

References (23)

1. Riento, K.; Ridley, A. J. ROCKs: Multifunctional kinases in cell behavior. Nat. Rev. Mol. Cell Biol. 2003, 4, 446-456. Two isoforms of Rho-kinase (ROCK1 or ROKβ and ROCK2 or ROKα) are known and they share >90% homology in the kinase domain. We have not observed differences in SAR between the two isoforms in the current chemical series (data not shown).
2. (a) Amano, M.; Fukata, Y.; Kaibuchi, K. Regulation and functions of Rho-associated kinase. Exp. Cell Res. 2000, 261, 44-51.
3. (b) Hu, E.; Lee, D. Rho kinase as a potential therapeutic target for cardiovascular diseases: Opportunities and challenges. Expert Opin. Ther. Targets 2005, 9, 715-736.
4. (c) Hu, E.; Lee, D. Rho kinase inhibitors as potential therapeutic agents for cardiovascular diseases. Curr. Opin. Invest. Drugs 2003, 4, 1065-1075.
5. (d) Hirooka, Y.; Shimokawa, H. Therapeutic potential of Rho-kinase inhibitors in cardiovascular diseases. Am. J. Cardiovasc. Drugs 2005, 5, 31-39.
6. (e) Lee, D. L.; Webb, R. C.; Jin, L. Hypertension and RhoA/Rho-kinase signaling in the vasculature: highlights from the recent literature. Hypertension 2004, 44, 796-799.
7. (f) Rikitake, Y.; Liao, J. K. ROCKs as therapeutic targets in cardiovascular diseases. Expert Rev. Cardiovasc. Ther. 2005, 3, 441-451.
8. (g) Teixeira, C. B.; Webb, R. C. Targeting the vascular RhoA-Rho-kinase signaling pathway in hypertension. Drug Discovery Today: Ther. Strat. 2005, 2, 193-199.
9. 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.
10. For, the expression, purification of ROCK1 and details on assay development, see: Khandekar, S. S.; Yi, T.; Dul, E.; Wright, L. L.; Chen, S.; Scott, G. F.; Smith, G. K.; Lee, D.; Hu, E.; Kirkpatrick, R. B. Expression, purification, and characterization of an enzymatically active truncated human Rho-kinase I (ROCK1) domain expressed in Sf-9 insect cells. Protein Pept. Lett. 2006, 13, 413-420.
11. Inhibition of RSK1 or p70S6K has been implicated in a number of cellular functions. Although the specific consequence of inhibition is not clearly understood, knowing the cross-activity of this series, we sought to remove the activities against these targets. For a leading reference on RSK1, see: Hauge, C.; Fröden, M. RSK and MSK in MAP kinase signalling. J. Cell Sci. 2006, 119, 3021-3033.
12. For a leading reference on p70S6K, see: Berven, L. A.; Crouch, M. F. Cellular function of p70S6K: A role in regulating cell motility. Immunol. Cell Biol. 2000, 78, 447-451.
13. (a) Bamford, M. J.; Alberti, M. J.; Bailey, N.; Davies, S.; Dean, D. K.; Gaiba, A.; Garland, S.; Harling, J. D.; Jung, D. K.; Panchal, T. A.; Parr, C. A.; Steadman, J. G.; Takle, A. K.; Townsend, J. T.; Wilson, D. M.; Witherington, J. (1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: A novel class of potent MSK-1-inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 3402-3406.
14. (b) Bamford, M. J.; Bailey, N.; Davies, S.; Dean, D. K.; Francis, L.; Panchal, T. A.; Parr, C. A.; Sehmi, S.; Steadman, J. G.; Takle, A. K.; Townsend, J. T.; Wilson, D. M. (1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5- oxadiazol-3-ylamine derivatives: Further optimisation as highly potent and selective MSK-1-inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 3407-3411.
15. For studies on aminofurazan-based GSK3 inhibitors, see: (a) Olesen, P. H.; Sorensen, A. R.; Urso, B.; Kurtzhals, P.; Bowler, A. N.; Ehrbar, U.; Hansen, B. F. Synthesis and in vitro characterization of 1-(4-aminofurazan-3-yl)-5- dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic acid derivatives. A new class of selective GSK-3 inhibitors. J. Med. Chem. 2003, 46, 3333-3341.
16. (b) Pande, V.; Ramos, M. J. Structural basis for the GSK-3beta binding affinity and selectivity against CDK-2 of 1-(4-aminofurazan-3yl)-5- dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic acid derivatives. Bioorg. Med. Chem. Lett. 2005, 15, 5129-5135.
17. Makosza, M.; Sienkiewicz, K. Hydroxylation of nitroarenes with alkyl hydroperoxide anions via vicarious nucleophilic substitution of hydrogen. J. Org. Chem. 1998, 63, 4199-4208.
18. (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Copper-catalyzed coupling of aryl iodides with aliphatic alcohols. Org. Lett. 2002, 4, 973-976.
19. (b) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. A general copper-catalyzed synthesis of diaryl ethers. J. Am. Chem. Soc. 1997, 119, 10539-10540.
20. The crystal structure of ROCK1 with several unrelated inhibitors was recently published: Jacobs, M.; Hayakawa, K.; Swenson, L.; Bellon, S.; Fleming, M.; Taslimi, P.; Doran, J. The structure of dimeric ROCK1 reveals the mechanism for ligand selectivity. J. Biol. Chem. 2006, 281, 260-268.
21. The homology model of the kinase domain of ROCK1 (residues 71-374 of the full-length ROCK1 sequence) was built in MOE (Molecular Operating Environment, Chemical Computing Group, Inc.) using the Engh-Huber force field. A crystal structure of cyclic AMP kinase (CAMPk, PDB code 113r) was used as the structural template; the aminofurazan ligand was manually docked into the CAMPk crystal structure and was included as part of the environment during model building.
22. Plasma levels were obtained for a 3 mg/kg dose of 6n in a satellite group of spontaneously hypertensive rats (n = 3). T = 0.5 h, 280 ± 23 ng/mL; T = 1 h, 330 ± 15 ng/mL; T = 2 h, 290 ± 24 ng/mL; T = 4 h, 150 ± 40 ng/mL; T = 8 h, 88 ± 20 ng/mL.
23. Fasudil (11) is 5-(hexahydro-1H-1,4-diazepin-1-ylsulfonyl)- quinoline.