4-Amino-2-cyanopyrimidines: novel scaffold for nonpeptidic cathepsin S inhibitors.
We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.
Irie
Osamu
O
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan. osamu.irie@novartis.com
Yokokawa
Fumiaki
F
Ehara
Takeru
T
Iwasaki
Atsuko
A
Iwaki
Yuki
Y
Hitomi
Yuko
Y
Konishi
Kazuhide
K
Kishida
Masashi
M
Toyao
Atsushi
A
Masuya
Keiichi
K
Gunji
Hiroki
H
Sakaki
Junichi
J
Iwasaki
Genji
G
Hirao
Hajime
H
Kanazawa
Takanori
T
Tanabe
Keiko
K
Kosaka
Takatoshi
T
Hart
Terance W
TW
Hallett
Allan
A
D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008968:Molecular Conformation; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D010455:Peptides; D011743:Pyrimidines; D011994:Recombinant Proteins; D002403:Cathepsins; C028217:cathepsin S