title: Detailed structure-activity relationship of indolecarboxamides as H4 receptor ligands.
abstract: A series of 76 derivatives of the indolecarboxamide 1 were synthesized, which allows a detailed SAR investigation of this well known scaffold. The data enable the definition of a predictive QSAR model which identifies several compounds with an activity comparable to 1. A selection of these new H(4)R antagonists was synthesized and a comparison of predicted and measured values demonstrates the robustness of the model (47-55). In addition to the H(4)-receptor activity general CMC and DMPK properties were investigated. Some of the new analogs are not only excellently soluble, but display a significantly increased half-life in mouse liver microsomes as well. These properties qualify these compounds as a possible new standard for future in vivo studies (e.g 51, 52 and 55). Moreover, the current studies also provide valuable information on the potential receptor ligand interactions between the indolcarboxamides and the H(4)R protein.
authors: Boehringer Ingelheim RCV GmbH & Co KG, Department of Medicinal Chemistry, Dr. Boehringergasse 5-11, Vienna, Austria.
authors: Harald
authors: H
authors: Engelhardt
authors: Iwan J P
authors: IJ
authors: de Esch
authors: Daniel
authors: D
authors: Kuhn
authors: Rogier A
authors: RA
authors: Smits
authors: Obbe P
authors: OP
authors: Zuiderveld
authors: Julia
authors: J
authors: Dobler
authors: Moriz
authors: M
authors: Mayer
authors: Sebastian
authors: S
authors: Lips
authors: Heribert
authors: H
authors: Arnhof
authors: Dirk
authors: D
authors: Scharn
authors: Eric E J
authors: EE
authors: Haaksma
authors: Rob
authors: R
authors: Leurs
mesh_terms: D000818:Animals; D004355:Drug Stability; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C418607:HRH4 protein, human; D007211:Indoles; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4