2. Academic Validation
  3. Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels

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

  • J Med Chem. 2008 Oct 23;51(20):6471-7. doi: 10.1021/jm800830n.
Zhi-Qiang Yang 1,  James C Barrow,  William D Shipe,  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 Adarayan,  Thomayant 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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. zhiqiang_yang@merck.com
PMID: 18817368 DOI: 10.1021/jm800830n
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 microM. 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.

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