Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 2. Synthesis and Structure−Activity Relationships of α,α-Cycloalkylglycine Sulfonamides
Autor: | Sandro Giuliani, Cristina Rossi, Valerio Caciagli, Laura Quartara, Rossano Nannicini, Stefania Meini, Alessandro Bressan, Daniela Fattori, Christopher I. Fincham, Fernando Catrambone, Piero D’Andrea, Elena Marastoni, Carlo Alberto Maggi, Claudio Valenti, Rosa Terracciano, Martina Gensini, Patrizia Felicetti, Marielle Paris |
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Rok vydání: | 2007 |
Předmět: |
Male
Ornithine Bronchoconstriction Inositol Phosphates Guinea Pigs Bradykinin Blood Pressure CHO Cells In Vitro Techniques Pharmacology Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Cricetulus Ileum In vivo Cricetinae Bradykinin B2 Receptor Antagonists Drug Discovery medicine Animals Humans Receptor Sulfonamides Sulfonamide (medicine) Antagonist Muscle Smooth Stereoisomerism Bronchodilator Agents chemistry Biochemistry Drug Design Molecular Medicine medicine.symptom B2 Bradykinin Receptor Muscle Contraction medicine.drug |
Zdroj: | Journal of Medicinal Chemistry. 50:550-565 |
ISSN: | 1520-4804 0022-2623 |
Popis: | Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation. |
Databáze: | OpenAIRE |
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