| Literature DB >> 18817368 |
Zhi-Qiang Yang1, 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.
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.Entities:
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Year: 2008 PMID： 18817368 DOI： 10.1021/jm800830n
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446