Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2.
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.
Irie
Osamu
O
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan. osamu.irie@novartis.com
Kosaka
Takatoshi
T
Kishida
Masashi
M
Sakaki
Junichi
J
Masuya
Keiichi
K
Konishi
Kazuhide
K
Yokokawa
Fumiaki
F
Ehara
Takeru
T
Iwasaki
Atsuko
A
Iwaki
Yuki
Y
Hitomi
Yuko
Y
Toyao
Atsushi
A
Gunji
Hiroki
H
Teno
Naoki
N
Iwasaki
Genji
G
Hirao
Hajime
H
Kanazawa
Takanori
T
Tanabe
Keiko
K
Hiestand
Peter C
PC
Malcangio
Marzia
M
Fox
Alyson J
AJ
Bevan
Stuart J
SJ
Yaqoob
Mohammed
M
Culshaw
Andrew J
AJ
Hart
Terance W
TW
Hallett
Allan
A
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
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