title: 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.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan. osamu.irie@novartis.com
authors.forename: Osamu
authors.initials: O
authors.lastname: Irie
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kosaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Kishida
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakaki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Masuya
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Konishi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokokawa
authors.forename: Takeru
authors.initials: T
authors.lastname: Ehara
authors.forename: Atsuko
authors.initials: A
authors.lastname: Iwasaki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Iwaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hitomi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyao
authors.forename: Hiroki
authors.initials: H
authors.lastname: Gunji
authors.forename: Naoki
authors.initials: N
authors.lastname: Teno
authors.forename: Genji
authors.initials: G
authors.lastname: Iwasaki
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirao
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Tanabe
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hiestand
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
authors.forename: Alyson J
authors.initials: AJ
authors.lastname: Fox
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Bevan
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yaqoob
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Culshaw
authors.forename: Terance W
authors.initials: TW
authors.lastname: Hart
authors.forename: Allan
authors.initials: A
authors.lastname: Hallett
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D003546:Cysteine Endopeptidases; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy; D010146:Pain / Q000188:drug therapy; D011743:Pyrimidines / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D011743:Pyrimidines; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534280:Ctsl protein, rat; C028217:cathepsin S