Discovery and characterization of novel, potent, non-peptide parathyroid hormone-1 receptor antagonists.
A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.
McDonald
Iain M
IM
James Black Foundation, 68 Half Moon Lane, Dulwich, London, SE24 9JE, UK. iain.mcdonald@kcl.ac.uk
Austin
Carol
C
Buck
Ildiko M
IM
Dunstone
David J
DJ
Gaffen
John
J
Griffin
Eric
E
Harper
Elaine A
EA
Hull
Robert A D
RA
Kalindjian
S Barret
SB
Linney
Ian D
ID
Low
Caroline M R
CM
Patel
Dipa
D
Pether
Michael J
MJ
Raynor
Michelle
M
Roberts
Sonia P
SP
Shaxted
Mark E
ME
Spencer
John
J
Steel
Katherine I M
KI
Sykes
David A
DA
Wright
Paul T
PT
Xun
Wei
W
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D011869:Radioligand Assay; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D001552:Benzazepines; D044168:Receptor, Parathyroid Hormone, Type 1; D011994:Recombinant Proteins; D000242:Cyclic AMP