Referenced in: none

Automatically associated channels: Kv11.1

Title: Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2.

Authors: Osamu Irie, Takatoshi Kosaka, Masashi Kishida, Junichi Sakaki, Keiichi Masuya, Kazuhide Konishi, Fumiaki Yokokawa, Takeru Ehara, Atsuko Iwasaki, Yuki Iwaki, Yuko Hitomi, Atsushi Toyao, Hiroki Gunji, Naoki Teno, Genji Iwasaki, Hajime Hirao, Takanori Kanazawa, Keiko Tanabe, Peter C Hiestand, Marzia Malcangio, Alyson J Fox, Stuart J Bevan, Mohammed Yaqoob, Andrew J Culshaw, Terance W Hart, Allan Hallett

Journal, date & volume: Bioorg. Med. Chem. Lett., 2008 Oct 1 , 18, 5280-4

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18783943

Abstract
We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.