Discovery of a dihydropyrimidine series of molecules that selectively mimic the biological actions of calcitonin.
The use of a multiplex mimetic assay led us to identify 1,4-dihydropyrimidines with potent and selective calcitonin receptor mimetic activity. Subsequent modification of the dihydropyrimidine scaffold led to a series of molecules that were efficacious in a neonatal mouse calvaria in vitro model. Dihydropyrimidine 5h, in particular, was identified as a calcitonin mimetic (EC(50)=6 microM), active in-vivo in the Weanling rat model when administered subcutaneously.
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. jmatthew@pruis.jnj.com
Jay M
JM
Matthews
Fina
F
Liotta
William
W
Hageman
Ralph A
RA
Rivero
Lori
L
Westover
Maria
M
Yang
Jun
J
Xu
Keith
K
Demarest
D000818:Animals; D002116:Calcitonin / Q000737:chemistry* / Q000502:physiology* / Q000652:urine; D002460:Cell Line; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology / Q000652:urine; D006801:Humans; D018716:Molecular Mimicry / Q000502:physiology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology / Q000652:urine; D051381:Rats
D004095:Dihydropyridines; D011743:Pyrimidines; D002116:Calcitonin