- Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist
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A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
- Haga, Yuji,Sakamoto, Toshihiro,Shibata, Takunobu,Nonoshita, Katsumasa,Ishikawa, Makoto,Suga, Takuya,Takahashi, Hirobumi,Takahashi, Toshiyuki,Takahashi, Hidekazu,Ando, Makoto,Murai, Takashi,Gomori, Akira,Oda, Zenjun,Kitazawa, Hidefumi,Mitobe, Yuko,Kanesaka, Maki,Ohe, Tomoyuki,Iwaasa, Hisashi,Ishii, Yasuyuki,Ishihara, Akane,Kanatani, Akio,Fukami, Takehiro
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experimental part
p. 6971 - 6982
(2010/02/28)
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- Identification of positron emission tomography ligands for NPY Y5 receptors in the brain
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A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized and profiled for NPY Y5 binding affinity, brain and CSF penetrability in rats, and susceptibility to human and mouse P-glycoprotein transporters in order to develop a PET ligand. Compound 12b exhibited an acceptable profile for a PET ligand, and [11C]12b was successfully utilized in clinical settings as a Y5 PET ligand.
- Takahashi, Hirobumi,Haga, Yuji,Shibata, Takunobu,Nonoshita, Katsumasa,Sakamoto, Toshihiro,Moriya, Minoru,Ohe, Tomoyuki,Chiba, Masato,Mitobe, Yuko,Kitazawa, Hidefumi,Iwaasa, Hisashi,Ishihara, Akane,Ishii, Yasuyuki,Kanatani, Akio,Fukami, Takehiro
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scheme or table
p. 5436 - 5439
(2010/05/19)
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- Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3 receptor inverse agonists
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Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t-x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H3 activity (IC50 = 0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC50 of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H3 inverse agonists.
- Jitsuoka, Makoto,Tsukahara, Daisuke,Ito, Sayaka,Tanaka, Takeshi,Takenaga, Norihiro,Tokita, Shigeru,Sato, Nagaaki
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scheme or table
p. 5101 - 5106
(2009/05/07)
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- Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists
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Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1′-cyclohexan]-4′-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC50 = 3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC50 = 5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists. Crown Copyright
- Ogino, Yoshio,Ohtake, Norikazu,Nagae, Yoshikazu,Matsuda, Kenji,Ishikawa, Makoto,Moriya, Minoru,Kanesaka, Maki,Mitobe, Yuko,Ito, Junko,Kanno, Tetsuya,Ishihara, Akane,Iwaasa, Hisashi,Ohe, Tomoyuki,Kanatani, Akio,Fukami, Takehiro
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scheme or table
p. 4997 - 5001
(2009/06/30)
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- Novel spiro compounds
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Compounds of the general formula (I): wherein Ar1 represents optionally substituted aryl or heteroaryl; n represents 0 or 1; T, U, V, and W each independently represent nitrogen atom or optionally substituted methine group, where at least two of them represent the said methine group; X represents methine or hydroxy substituted methine; Y represents an optionally substituted imino or oxygen atom are described and claimed. These novel spiro compounds are useful as neuropeptide Y receptor antagonists and as agents for the treatment of various kinds of cardiovascular disorders, central nervous system disorders, metabolic diseases and the like.
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