Thienopyrimidines as β3-adrenoceptor agonists: hit-to-lead optimization.
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.
Tasler
Stefan
S
4SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany. stefan.tasler@4sc.com
Baumgartner
Roland
R
Ammendola
Astrid
A
Schachtner
Josef
J
Wieber
Tanja
T
Blisse
Marcus
M
Rath
Sandra
S
Zaja
Mirko
M
Klahn
Philipp
P
Quotschalla
Udo
U
Ney
Peter
P
D058673:Adrenergic beta-3 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival; D015195:Drug Design; D006801:Humans; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*
D058673:Adrenergic beta-3 Receptor Antagonists; D011743:Pyrimidines; D022702:Receptors, Adrenergic, beta-3; C476003:thienopyrimidine