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Rapid and straightforward transesterification of sulfonyl carbamates
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
2016 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, no 13, p. 1476-1478Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

A fast and convenient method for the alkoxy exchange of sulfonyl carbamates by simply heating in a chosen alkyl alcohol is described. No catalysts or additives are required. Microwave heating at 100-120 degrees C for 20-60 min resulted in good to excellent yields (53-93%) of alkyl (arylsulfonyl)carbamates where the alkyl part originates from the alcohol solvent. The developed protocol was applied to the synthesis of an angiotensin II type 2 receptor (AT2R) ligand.

Place, publisher, year, edition, pages
2016. Vol. 57, no 13, p. 1476-1478
Keywords [en]
Sulfonyl carbamates, O-alkyl exchange, Transesterification, Carboxylic acid bioisosteres, AT2R ligand
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-294300DOI: 10.1016/j.tetlet.2016.02.071ISI: 000372690800018OAI: oai:DiVA.org:uu-294300DiVA, id: diva2:929566
Funder
EU, FP7, Seventh Framework Programme, REGPOT-CT-2013-316149-InnovaBaltAvailable from: 2016-05-19 Created: 2016-05-18 Last updated: 2019-04-04Bibliographically approved
In thesis
1. Ligands of the Angiotensin II Type 2 Receptor: Exploring structure and function of the AT2R ligand C38
Open this publication in new window or tab >>Ligands of the Angiotensin II Type 2 Receptor: Exploring structure and function of the AT2R ligand C38
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The renin-angiotensin-aldosterone-system (RAAS) control blood-pressure regulation, exerted by the main effector peptide angiotensin II (AngII) binding the angiotensin II type 1 receptor (AT1R). While hypertension is the most known disease caused by over-activity in RAAS, several proteins in the system exhibit protective functions.

One of these protective proteins is the GPCR angiotensin II type 2 receptor (AT2R). After decades of research its biological role remain to be fully elucidated, exemplified by the two AT2R ligands currently in clinical trials; agonist C21 for treatment of idiopathic pulmonary fibrosis, and antagonist EMA401 for treatment of peripheral neuropathic pain. Making a minor structural change in C21 shifted the pharmacological profile, generating the regioisomer antagonist C38. The renewed interest in AT2R antagonists as potential drugs to treat neuropathic pain make continued studies of antagonist C38 highly interesting. 

The aim of this thesis was to continue exploring the structure-activity relationship of antagonist C38 by investigating three chemical motifs to identify compounds with better drug-like properties. Developing a new chemical method, transesterification of sulfonyl carbamates, allowed quick modification of one of the motifs. Reducing the length of the sulfonyl carbamate chain significantly increased metabolic stability in liver microsomes without losing affinity for AT2R. Using a model substrate, the transesterification reaction was applied in a microwave heated continuous-flow system.

Adding small substituents to the central phenyl ring generated a second library of ligands with retained affinity, but with no observed increase in metabolic stability. Docking studies with this library and a recently presented crystal structure of AT2R, resulted in a proposed binding mode of C38. Replacing the imidazole head group with bicyclic amides slightly improved affinity. While metabolic stability improved compared to previously published amide analogs, the bicyclic ligands were inferior to C38. Developing an assay based on RAW264.7 macrophages allowed a new evaluation of the functional activity exhibited by C38. In contrast to previous research, C21 and C38 both display agonistic functional activity in the macrophage assay.

In summary, the work presented in this thesis expand the structure-activity relationship of C38 and its pharmacological profile. Two new ligands were identified that could serve as tools in murine models of neuropathic pain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 74
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 269
Keywords
Angiotensin II type 2 receptor, AT2R antagonists, sulfonyl carbamates, bicyclic amides, metabolic stability, functional activity assay, pharmacological profile, medicinal chemistry, structure-activity relationship
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-381102 (URN)978-91-513-0630-8 (ISBN)
Public defence
2019-05-29, Room A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-05-07 Created: 2019-04-04 Last updated: 2019-05-07

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Isaksson, RebeckaLarhed, MatsWannberg, Johan

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