Identification of 3,4-dihydro-2 H -thiochromene 1,1-dioxide derivatives with a phenoxyethylamine group as highly potent and selective α 1D adrenoceptor antagonists
| Autor: | Junya Shirai, Masato Yoshida, Ayumu Sato, Nobuki Sakauchi, Haruhiko Kuno, Reiko Saikawa, Hideki Furukawa |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology Adrenergic receptor Stereochemistry Xantphos Organic Chemistry Antagonist General Medicine α1d adrenoceptor 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry XPhos 030220 oncology & carcinogenesis Drug Discovery Potency Structure–activity relationship Selectivity |
| Zdroj: | European Journal of Medicinal Chemistry. 139:114-127 |
| ISSN: | 0223-5234 |
| Popis: | A series of phenoxyethylamine derivatives was designed and synthesized to discover potent and selective human α 1D adrenoceptor (α 1D adrenergic receptor; α 1D –AR) antagonists. Compound 7 was taken from our internal compound collection as an attractive starting point and exhibited moderate binding affinity for α 1D –AR and high selectivity against α 1A – and α 1B –ARs. We focused on modifying the 2-methylsulfonylbenzyl group of 7 to discover novel compounds structurally distinct from other reported α 1 –AR antagonists containing the phenoxyethylamine motif. Study of structure activity relationship guided by a targeted ligand-lipophilicity efficiency score led to the discovery of a novel scaffold of 3,4-dihydro-2 H -thiochromene 1,1-dioxide for selective α 1D –AR antagonists. Further optimization studies resulted in the identification of (4 S )- N 4 -[2-(2,5-difluorophenoxy)ethyl]- N 6 -methyl-3,4-dihydro-2 H -thiochromene-4,6-diamine 1,1-dioxide, ( S )– 41 , as a novel, highly potent and selective α 1D –AR antagonist. Herein, we provide details of the structure activity relationship of the phenoxyethylamine analog for the potency and selectivity. |
| Databáze: | OpenAIRE |
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