Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part II)
| Autor: | Czechtizky Werngard, Raisa Nagorny, Zhongli Gao, Hendrix James A, Siegfried Stengelin, Lothar Schwink, Pascal George, Marie-Pierre Pruniaux, Lei Tang, Irvin Winkler, Juan Antonio Sánchez, Ulrike Lukasczyk, Etienne Guillot, Hurst William J |
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| Rok vydání: | 2013 |
| Předmět: |
Pyrrolidines
Drug Inverse Agonism Stereochemistry Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Administration Oral Plasma protein binding Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Microsomes Drug Discovery Structure–activity relationship Animals Humans Receptors Histamine H3 Urea Obesity Receptor Molecular Biology Aryl HEK 293 cells Organic Chemistry Macaca mulatta Amides In vitro Rats HEK293 Cells chemistry Benzamides Molecular Medicine Histamine H3 receptor Caco-2 Cells Antagonism Histamine H3 Antagonists Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry letters. 23(11) |
| ISSN: | 1464-3405 |
| Popis: | A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization. |
| Databáze: | OpenAIRE |
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