A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes

Johan Wannberg; Rebecka Isaksson; Ulf Bremberg; Maria Backlund; Jonas Sävmarker; Mathias Hallberg; Mats Larhed

doi:10.1016/j.bmcl.2017.11.042

A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes

Bioorg Med Chem Lett. 2018 Feb 1;28(3):519-522. doi: 10.1016/j.bmcl.2017.11.042. Epub 2017 Nov 24.

Authors

Johan Wannberg¹, Rebecka Isaksson², Ulf Bremberg¹, Maria Backlund³, Jonas Sävmarker⁴, Mathias Hallberg⁵, Mats Larhed⁶

Affiliations

¹ Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
² Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
³ Department of Pharmacy, Uppsala University, Uppsala, Sweden and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Science for Life Laboratory, Uppsala, Sweden.
⁴ The Beijer Laboratory, Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.
⁵ The Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, BMC, Uppsala University, P.O. Box 591, SE-751 24 Uppsala, Sweden.
⁶ Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden. Electronic address: mats.larhed@orgfarm.uu.se.

PMID: 29279275
DOI: 10.1016/j.bmcl.2017.11.042

Abstract

A series of AT₂R ligands have been synthesized applying a quick, simple, and safe transesterification-type reaction whereby the sulfonyl carbamate alkyl tail of the selective AT₂R antagonist C38 was varied. Furthermore, a limited number of compounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acid bioisosteres were synthesized and evaluated. By reducing the size of the alkyl chain of the sulfonyl carbamates, ligands 7a and 7b were identified with significantly improved in vitro metabolic stability in both human and mouse liver microsomes as compared to C38 while retaining the AT₂R binding affinity and AT₂R/AT₁R selectivity. Eight of the compounds synthesized exhibit an improved stability in human microsomes as compared to C38.

Keywords: AT(2)R antagonists; Angiotensin II type 2 receptor antagonists; Liver microsomes; Sulfonyl carbamates; Transesterification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Esters / chemical synthesis
Esters / chemistry
Esters / pharmacology*
Humans
Ligands
Microsomes, Liver / chemistry*
Microsomes, Liver / metabolism
Molecular Structure
Receptor, Angiotensin, Type 2 / metabolism*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*

Substances

Esters
Ligands
Receptor, Angiotensin, Type 2
Sulfonamides
Urea