Muscarinic M3 Receptor Antagonists with (2R)-2-[(1R)-3,3-Difluorocyclopentyl]-2-hydroxyphenylacetamide Structures. Part 2
| Autor: | Norikazu Ohtake, Toshiaki Mase, Kensuke Kobayashi, Takuro Hasegawa, Yoshio Ogino, Kazuhito Noguchi, Toru Fujikawa, Toshifumi Kimura |
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| Rok vydání: | 2003 |
| Předmět: |
medicine.drug_class
Stereochemistry Clinical Biochemistry Substituent Pharmaceutical Science Carboxamide CHO Cells Cyclopentanes Muscarinic Antagonists Transfection Biochemistry Structure-Activity Relationship chemistry.chemical_compound Dogs Cricetinae Diamine Drug Discovery Acetamides Muscarinic acetylcholine receptor medicine Animals Humans Receptor Molecular Biology Receptor Muscarinic M3 Organic Chemistry Muscarinic acetylcholine receptor M3 General Medicine Receptor antagonist Rats Kinetics chemistry Area Under Curve Microsomes Liver Molecular Medicine Indicators and Reagents Amine gas treating Selectivity |
| Zdroj: | ChemInform. 34 |
| ISSN: | 1522-2667 0931-7597 |
| DOI: | 10.1002/chin.200343121 |
| Popis: | Optimization of the amine part of our original muscarinic M(3) receptor antagonist 1 was performed to identify M(3) receptor antagonists that are superior to 1. Compounds carrying a variety of diamine moieties without hydrophobic substituent on the nitrogen atom were screened against the binding affinity for the M(3) receptor and the selectivity for M(3) over the M(1) and M(2) receptors. This process led to a 4-aminopiperidinamide (2l) with a K(i) value of 5.1 nM and with a selectivity of the M(3) receptor that was 46-fold greater than that of the M(2) receptor. Further derivatization of 2l by inserting a spacer group or by incorporating alkyl group(s) into the amine part resulted in the identification of an 4-(aminoethyl)piperidinamide 2l-b with a K(i) value of 3.7 nM for the M(3) receptor and a selectivity for the M(3) receptor that was 170-fold greater than that of the M(2) receptor. |
| Databáze: | OpenAIRE |
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