Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels

Zhi Qiang Yang, James C. Barrow, William D. Snipe, Kelly Ann S. Schlegel, Youheng Shu, F. Vivien Yang, Craig W. Lindsley, Kenneth E. Rittle, Mark G. Bock, George D. Hartman, Victor N. Uebele, Cindy E. Nuss, Steve V. Fox, Richard L. Kraus, Scott M. Doran, Thomas M. Connolly, Cuyue Tang, Jeanine E. Ballard, Yuhsin Kuo, Emily D. AdarayanThomayant Prueksaritanont, Matthew M. Zrada, Michael J. Marino, Valerie Kuzmick Graufelds, Anthony G. DiLella, Ian J. Reynolds, Hugo M. Vargas, Patricia B. Bunting, Richard F. Woltmann, Michael M. Magee, Kenneth S. Koblan, John J. Renger

Research output: Contribution to journalArticle

Abstract

The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 μM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.

Original languageEnglish (US)
Pages (from-to)6471-6477
Number of pages7
JournalJournal of medicinal chemistry
Volume51
Issue number20
DOIs
StatePublished - Oct 23 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Yang, Z. Q., Barrow, J. C., Snipe, W. D., Schlegel, K. A. S., Shu, Y., Yang, F. V., Lindsley, C. W., Rittle, K. E., Bock, M. G., Hartman, G. D., Uebele, V. N., Nuss, C. E., Fox, S. V., Kraus, R. L., Doran, S. M., Connolly, T. M., Tang, C., Ballard, J. E., Kuo, Y., ... Renger, J. J. (2008). Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels. Journal of medicinal chemistry, 51(20), 6471-6477. https://doi.org/10.1021/jm800830n