title: 4-Amino-2-cyanopyrimidines: novel scaffold for nonpeptidic cathepsin S inhibitors.
abstract: 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.
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: 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: Kazuhide
authors.initials: K
authors.lastname: Konishi
authors.forename: Masashi
authors.initials: M
authors.lastname: Kishida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyao
authors.forename: Keiichi
authors.initials: K
authors.lastname: Masuya
authors.forename: Hiroki
authors.initials: H
authors.lastname: Gunji
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakaki
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: Takatoshi
authors.initials: T
authors.lastname: Kosaka
authors.forename: Terance W
authors.initials: TW
authors.lastname: Hart
authors.forename: Allan
authors.initials: A
authors.lastname: Hallett
mesh_terms: 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
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D010455:Peptides; D011743:Pyrimidines; D011994:Recombinant Proteins; D002403:Cathepsins; C028217:cathepsin S