title: Discovery of novel and orally active NR2B-selective N-methyl-D-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity.
abstract: Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).
authors.affiliation: Discovery Chemistry, Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan. makoto.kawai@pfizer.com
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Isao
authors.initials: I
authors.lastname: Sakurada
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tanaka
authors.forename: Miyako
authors.initials: M
authors.lastname: Matsumizu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ando
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hattori
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohta
authors.forename: Seiji
authors.initials: S
authors.lastname: Nukui
authors.forename: Atsushi
authors.initials: A
authors.lastname: Omura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawamura
mesh_terms: D000284:Administration, Oral; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C121001:NR2B NMDA receptor; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; C023666:pyridine