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

Steven J Taylor; Fariba Soleymanzadeh; Ingo Muegge; Isamu Akiba; Naoyuki Taki; Saisoku Ueda; Elizabeth Mainolfi; Anne B Eldrup

doi:10.1016/j.bmcl.2013.01.105

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

Bioorg Med Chem Lett. 2013 Apr 1;23(7):2177-80. doi: 10.1016/j.bmcl.2013.01.105. Epub 2013 Feb 4.

Authors

Steven J Taylor¹, Fariba Soleymanzadeh, Ingo Muegge, Isamu Akiba, Naoyuki Taki, Saisoku Ueda, Elizabeth Mainolfi, Anne B Eldrup

Affiliation

¹ Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877-036, USA. [email protected]

PMID: 23453841
DOI: 10.1016/j.bmcl.2013.01.105

Abstract

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.

MeSH terms

Benzylamines / chemical synthesis
Benzylamines / chemistry
Benzylamines / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Sulfones / chemical synthesis
Sulfones / chemistry
Sulfones / pharmacology*

Substances

Benzylamines
Receptors, G-Protein-Coupled
Sulfonamides
Sulfones
UTS2R protein, human
benzylamine