Synthesis and Structure−Activity Relationships of Novel Histamine H1 Antagonists: Indolylpiperidinyl Benzoic Acid Derivatives
| Autor: | Carles Puig, Jordi Gras, Elena Calaf, Arantxa Cardús, Lluís Pagès, Jorge Beleta, Montse Miralpeix, Francisca Antón, Graham Warrellow, Hamish Ryder, José Prieto, Alvaro Cardenas, Mònica Aparici, Silvia Fonquerna, Josep M. Huerta, Dolors Vilella |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Indoles Guinea Pigs In Vitro Techniques Chemical synthesis Capillary Permeability Electrocardiography Mice Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Piperidines In vivo Receptors Adrenergic alpha-1 Drug Discovery Animals Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Humans Potency Structure–activity relationship Receptors Histamine H1 Rats Wistar Skin Benzoic acid Antagonist Brain Histamine H1 Antagonists In vitro Rats Biochemistry chemistry Blood-Brain Barrier Receptors Serotonin Molecular Medicine Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 47:6326-6337 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation. |
| Databáze: | OpenAIRE |
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