| Title : Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493' - Shishido_2008_Bioorg.Med.Chem_16_7193 |
| Author(s) : Shishido Y , Wakabayashi H , Koike H , Ueno N , Nukui S , Yamagishi T , Murata Y , Naganeo F , Mizutani M , Shimada K , Fujiwara Y , Sakakibara A , Suga O , Kusano R , Ueda S , Kanai Y , Tsuchiya M , Satake K |
| Ref : Bioorganic & Medicinal Chemistry , 16 :7193 , 2008 |
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Abstract :
A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino- 2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721. |
| PubMedSearch : Shishido_2008_Bioorg.Med.Chem_16_7193 |
| PubMedID: 18640044 |
Shishido Y, Wakabayashi H, Koike H, Ueno N, Nukui S, Yamagishi T, Murata Y, Naganeo F, Mizutani M, Shimada K, Fujiwara Y, Sakakibara A, Suga O, Kusano R, Ueda S, Kanai Y, Tsuchiya M, Satake K (2008)
Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'
Bioorganic & Medicinal Chemistry
16 :7193
Shishido Y, Wakabayashi H, Koike H, Ueno N, Nukui S, Yamagishi T, Murata Y, Naganeo F, Mizutani M, Shimada K, Fujiwara Y, Sakakibara A, Suga O, Kusano R, Ueda S, Kanai Y, Tsuchiya M, Satake K (2008)
Bioorganic & Medicinal Chemistry
16 :7193