title: Synthesis and biological evaluation of imidazole derivatives as novel NOP/ORL1 receptor antagonists: exploration and optimization of alternative pyrazole structure.
abstract: Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett.2009, 19, 3627; Kobayashi et al., Bioorg. Med. Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group demonstrated that examining the structure-activity relationship for novel templates allowed the identification of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole. These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or reduced hERG affinity.
authors: Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba 300-2611, Ibaraki, Japan. yuichi_sugimoto@merck.com
authors: Yuichi
authors: Y
authors: Sugimoto
authors: Kensuke
authors: K
authors: Kobayashi
authors: Masanori
authors: M
authors: Asai
authors: Akio
authors: A
authors: Ohno
authors: Koji
authors: K
authors: Yamada
authors: Satoshi
authors: S
authors: Ozaki
authors: Hisashi
authors: H
authors: Ohta
authors: Osamu
authors: O
authors: Okamoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D009292:Narcotic Antagonists; D011720:Pyrazoles / Q000737:chemistry; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C496884:KCNH1 protein, human; D009292:Narcotic Antagonists; D011720:Pyrazoles; D011957:Receptors, Opioid; C031280:pyrazole; D000094942:Nociceptin Receptor