title: Discovery of potent and selective histamine H3 receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold.
abstract: A novel series of potent histamine H(3) receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold has been discovered. Several compounds display high selectivity over other histamine receptor subtypes and have favorable physicochemical properties, low potential for CYP450 enzyme inhibition and high metabolic stability in microsomal preparations. (R)-2-Cyclopropylmethyl-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (8t) showed good in vivo efficacy after per os application in an acute rat dipsogenia model of water intake.
authors.affiliation: F Hoffmann-La Roche Ltd, Pharmaceutical Research, Grenzacherstrasse, CH-4070 Basel, Switzerland. hans.richter@roche.com
authors.forename: H G F
authors.initials: HG
authors.lastname: Richter
authors.forename: C
authors.initials: C
authors.lastname: Freichel
authors.forename: J
authors.initials: J
authors.lastname: Huwyler
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
authors.forename: M
authors.initials: M
authors.lastname: Nettekoven
authors.forename: J-M
authors.initials: JM
authors.lastname: Plancher
authors.forename: S
authors.initials: S
authors.lastname: Raab
authors.forename: O
authors.initials: O
authors.lastname: Roche
authors.forename: F
authors.initials: F
authors.lastname: Schuler
authors.forename: S
authors.initials: S
authors.lastname: Taylor
authors.forename: C
authors.initials: C
authors.lastname: Ullmer
authors.forename: R
authors.initials: R
authors.lastname: Wiegand
mesh_terms: D000818:Animals; D003919:Diabetes Insipidus / Q000188:drug therapy; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D054314:Drug Inverse Agonism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007211:Indoles; D018100:Receptors, Histamine H3; D011994:Recombinant Proteins