title: Lead optimization of thiazolo[5,4-c]piperidines: 3-cyclobutoxy linker as a key spacer for H(3)R inverse agonists.
abstract: The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.
authors.affiliation: UCB NewMedicines, UCB Pharma, Chemin du Foriest, 1420 Braine-L'Alleud, Belgium. laurent.provins@ucb.com
authors.forename: Laurent
authors.initials: L
authors.lastname: Provins
authors.forename: Frédéric
authors.initials: F
authors.lastname: Denonne
authors.forename: Sylvain
authors.initials: S
authors.lastname: Célanire
authors.forename: Bernard
authors.initials: B
authors.lastname: Christophe
authors.forename: Sabine
authors.initials: S
authors.lastname: Defays
authors.forename: Christel
authors.initials: C
authors.lastname: Delaunoy
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Delporte
authors.forename: Thierry
authors.initials: T
authors.lastname: Demaude
authors.forename: Véronique
authors.initials: V
authors.lastname: Durieu
authors.forename: Michel
authors.initials: M
authors.lastname: Gillard
authors.forename: Delphine
authors.initials: D
authors.lastname: Hubert
authors.forename: Yves
authors.initials: Y
authors.lastname: Lamberty
authors.forename: Geneviève
authors.initials: G
authors.lastname: Lorent
authors.forename: Anne
authors.initials: A
authors.lastname: Valade
authors.forename: Alain
authors.initials: A
authors.lastname: Vanbellinghen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van Houtvin
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018938:Caco-2 Cells; D017442:Histamine Agonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: D001549:Benzamides; C072312:ERG protein, human; D017442:Histamine Agonists; D010880:Piperidines; D018100:Receptors, Histamine H3; D013844:Thiazoles; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG