Thienopyrimidines as β3-adrenoceptor agonists: hit-to-lead optimization

Stefan Tasler; Roland Baumgartner; Astrid Ammendola; Josef Schachtner; Tanja Wieber; Marcus Blisse; Sandra Rath; Mirko Zaja; Philipp Klahn; Udo Quotschalla; Peter Ney

doi:10.1016/j.bmcl.2010.08.039

Thienopyrimidines as β3-adrenoceptor agonists: hit-to-lead optimization

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6108-15. doi: 10.1016/j.bmcl.2010.08.039. Epub 2010 Aug 12.

Authors

Stefan Tasler¹, Roland Baumgartner, Astrid Ammendola, Josef Schachtner, Tanja Wieber, Marcus Blisse, Sandra Rath, Mirko Zaja, Philipp Klahn, Udo Quotschalla, Peter Ney

Affiliation

¹ 4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany. [email protected]

PMID: 20833036
DOI: 10.1016/j.bmcl.2010.08.039

Abstract

Resulting from a vHTS based on a pharmacophore alignment on known β3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human β3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over hβ1- and hβ2-adrenoceptors and a promising safety profile.

MeSH terms

Adrenergic beta-3 Receptor Antagonists / chemical synthesis
Adrenergic beta-3 Receptor Antagonists / chemistry*
Adrenergic beta-3 Receptor Antagonists / pharmacology*
Cell Line
Cell Survival
Drug Design
Humans
Protein Binding
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Receptors, Adrenergic, beta-3 / metabolism*

Substances

Adrenergic beta-3 Receptor Antagonists
Pyrimidines
Receptors, Adrenergic, beta-3
thienopyrimidine