title: 3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake-promoting activity.
abstract: A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development.
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA. Electronic address: robert.hudkins@tevapharm.com.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Becknell
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Lyons
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Olsen
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Haltiwanger
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.affiliation: Discovery and Product Development, Teva Global R&D., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054314:Drug Inverse Agonism; D006633:Histamine Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D006633:Histamine Antagonists; D011724:Pyridazines; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C561238:6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one
keywords: CEP-26401; H(3) inverse agonist; Histamine H(3) receptor; Irdabisant; Pyridazin-3-one; Sleep-wake