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

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.

• 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: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 19 Pg. 5280-4 (Oct 01 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18783943 (Publication Type: Journal Article)

Chemical References

• Ether-A-Go-Go Potassium Channels
• Pyrimidines
• Cathepsins
• Cysteine Endopeptidases
• CTSL protein, human
• Cathepsin L
• Ctsl protein, rat
• cathepsin S

Topics

• Administration, Oral
• Animals
• Brain (drug effects)
• Cathepsin L
• Cathepsins (antagonists & inhibitors)
• Combinatorial Chemistry Techniques
• Cysteine Endopeptidases
• Ether-A-Go-Go Potassium Channels (metabolism)
• Humans
• Male
• Molecular Structure
• Multiple Sclerosis (drug therapy)
• Pain (drug therapy)
• Pyrimidines (blood, chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship