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Osamu Irie,
Fumiaki Yokokawa,
Takeru Ehara,
Atsuko Iwasaki,
Yuki Iwaki,
Yuko Hitomi,
Kazuhide Konishi,
Masashi Kishida,
Atsushi Toyao,
Keiichi Masuya,
Hiroki Gunji, Junichi Sakaki,
Genji Iwasaki,
Hajime Hirao,
Takanori Kanazawa,
Keiko Tanabe,
Takatoshi Kosaka,
Terance W Hart,
Allan Hallett
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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.
Bioorganic & medicinal chemistry letters 09/2008; 18(16):4642-6. · 2.65 Impact Factor
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Osamu Irie,
Takatoshi Kosaka,
Masashi Kishida, Junichi Sakaki,
Keiichi Masuya,
Kazuhide Konishi,
Fumiaki Yokokawa,
Takeru Ehara,
Atsuko Iwasaki,
Yuki Iwaki, [......],
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
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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.
Bioorganic & medicinal chemistry letters 09/2008; 18(19):5280-4. · 2.65 Impact Factor
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Osamu Irie,
Takatoshi Kosaka,
Takeru Ehara,
Fumiaki Yokokawa,
Takanori Kanazawa,
Hajime Hirao,
Astuko Iwasaki, Junichi Sakaki,
Naoki Teno,
Yuko Hitomi, [......],
Keiko Tanabe,
Shinichi Koizumi,
Noriko Uchiyama,
Stuart J Bevan,
Marzia Malcangio,
Clive Gentry,
Alyson J Fox,
Mohammed Yaqoob,
Andrew J Culshaw,
Allan Hallett
[show abstract]
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ABSTRACT: Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.
Journal of Medicinal Chemistry 09/2008; 51(18):5502-5. · 4.80 Impact Factor
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Osamu Irie,
Takeru Ehara,
Atsuko Iwasaki,
Fumiaki Yokokawa, Junichi Sakaki,
Hajime Hirao,
Takanori Kanazawa,
Naoki Teno,
Miyuki Horiuchi,
Ichiro Umemura,
Hiroki Gunji,
Keiichi Masuya,
Yuko Hitomi,
Genji Iwasaki,
Kazuhiko Nonomura,
Keiko Tanabe,
Hiroaki Fukaya,
Takatoshi Kosaka,
Christopher R Snell,
Allan Hallett
[show abstract]
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ABSTRACT: Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.
Bioorganic & medicinal chemistry letters 08/2008; 18(14):3959-62. · 2.65 Impact Factor
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Naoki Teno,
Takahiro Miyake,
Takeru Ehara,
Osamu Irie, Junichi Sakaki,
Osamu Ohmori,
Hiroki Gunji,
Naoko Matsuura,
Keiichi Masuya,
Yuko Hitomi, [......],
Keigo Gohda,
Atsuko Iwasaki,
Ichiro Umemura,
Sachiyo Tada,
Motohiko Kometani,
Genji Iwasaki,
Sandra W Cowan-Jacob,
Martin Missbach,
René Lattmann,
Claudia Betschart
[show abstract]
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ABSTRACT: Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.
Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6096-100. · 2.55 Impact Factor
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ABSTRACT: Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.
Bioorganic & Medicinal Chemistry Letters 10/2007; 17(17):4808-11. · 2.55 Impact Factor
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Junichi Sakaki,
Masashi Kishida,
Kazuhide Konishi,
Hiroki Gunji,
Atsushi Toyao,
Yuki Matsumoto,
Takanori Kanazawa,
Hidefumi Uchiyama,
Hiroaki Fukaya,
Hironobu Mitani,
Yoshie Arai,
Masaaki Kimura
[show abstract]
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ABSTRACT: A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.
Bioorganic & Medicinal Chemistry Letters 10/2007; 17(17):4804-7. · 2.55 Impact Factor
