Deconstruction of sulfonamide inhibitors of the urotensin receptor (UT) and design and synthesis of benzylamine and benzylsulfone antagonists

Potent small molecule antagonists of the urotensin receptor are described. These inhibitors were derived via systematically deconstructing a literature inhibitor to understand the basic pharmacophore and key molecular features required to inhibit the protein receptor. The series of benzylamine and b...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (7), p.2177-2180
Main Authors: Taylor, Steven J., Soleymanzadeh, Fariba, Muegge, Ingo, Akiba, Isamu, Taki, Naoyuki, Ueda, Saisoku, Mainolfi, Elizabeth, Eldrup, Anne B.
Format: Article
Language:English
Subjects:
antagonists
Benzylamines
Benzylamines - chemical synthesis
Benzylamines - chemistry
Benzylamines - pharmacology
Benzylsulfones
Cardiovascular disease
chemistry
Dose-Response Relationship, Drug
Drug Design
Humans
Molecular Structure
permeability
pharmacology
Receptors, G-Protein-Coupled - antagonists & inhibitors
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
Sulfones - chemical synthesis
Sulfones - chemistry
Sulfones - pharmacology
Urotensin II
Urotensin receptor
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Summary:Potent small molecule antagonists of the urotensin receptor are described. These inhibitors were derived via systematically deconstructing a literature inhibitor to understand the basic pharmacophore and key molecular features required to inhibit the protein receptor. The series of benzylamine and benzylsulfone antagonists herein reported display a combination of nanomolar molecular and cellular potency as well as acceptable in vitro permeability and metabolic stability.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.01.105