title: Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H₁-antihistamines for insomnia.
abstract: The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.
authors.affiliation: Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA. satheesh.ravula@gmail.com
authors.forename: Satheesh Babu
authors.initials: SB
authors.lastname: Ravula
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Melissa
authors.initials: M
authors.lastname: Arellano
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Wilna J
authors.initials: WJ
authors.lastname: Moree
authors.forename: Bin-Feng
authors.initials: BF
authors.lastname: Li
authors.forename: Robert E
authors.initials: RE
authors.lastname: Petroski
authors.forename: Jianyun
authors.initials: J
authors.lastname: Wen
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.forename: Samuel R J
authors.initials: SR
authors.lastname: Hoare
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: Graham
authors.initials: G
authors.lastname: Beaton
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects; D008956:Models, Chemical; D009025:Morpholines / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011969:Receptors, Histamine H1 / Q000737:chemistry; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D006993:Hypnotics and Sedatives; D009025:Morpholines; D010880:Piperidines; D011969:Receptors, Histamine H1; D009584:Nitrogen