title: Design of a new histamine H3 receptor antagonist chemotype: (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, synthesis, and structure-activity relationships.
abstract: A new histamine H3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based on a previously identified conessine-based H3R antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H3 K(i) of 0.54 nM, rat H3 K(i) of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t(1/2) of 2.4 h).
authors: Department of Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6123, USA. chen.zhao@abbott.com
authors: Chen
authors: C
authors: Zhao
authors: Minghua
authors: M
authors: Sun
authors: Youssef L
authors: YL
authors: Bennani
authors: Thomas R
authors: TR
authors: Miller
authors: David G
authors: DG
authors: Witte
authors: Timothy A
authors: TA
authors: Esbenshade
authors: Jill
authors: J
authors: Wetter
authors: Kennan C
authors: KC
authors: Marsh
authors: Arthur A
authors: AA
authors: Hancock
authors: Jorge D
authors: JD
authors: Brioni
authors: Marlon D
authors: MD
authors: Cowart
mesh_terms: D000818:Animals; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D054828:Histamine H3 Antagonists; D011758:Pyrroles