title: 5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity.
abstract: Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed.
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, CH-4070 Basel, Switzerland.
authors.forename: Pascale David
authors.initials: PD
authors.lastname: Pierson
authors.forename: Alec
authors.initials: A
authors.lastname: Fettes
authors.forename: Christian
authors.initials: C
authors.lastname: Freichel
authors.forename: Silvia
authors.initials: S
authors.lastname: Gatti-McArthur
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hertel
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.forename: Toshito
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Matthias
authors.initials: M
authors.lastname: Nettekoven
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Plancher
authors.forename: Susanne
authors.initials: S
authors.lastname: Raab
authors.forename: Hans
authors.initials: H
authors.lastname: Richter
authors.forename: Olivier
authors.initials: O
authors.lastname: Roche
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Rodríguez Sarmiento
authors.forename: Monique
authors.initials: M
authors.lastname: Schmitt
authors.forename: Franz
authors.initials: F
authors.lastname: Schuler
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Sven
authors.initials: S
authors.lastname: Taylor
authors.forename: Christoph
authors.initials: C
authors.lastname: Ullmer
authors.forename: Ruby
authors.initials: R
authors.lastname: Wiegand
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D002463:Cell Membrane Permeability; D019295:Computational Biology; D015195:Drug Design; D017442:Histamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D017442:Histamine Agonists; D007211:Indoles; D018100:Receptors, Histamine H3