Nonsteroidal progesterone receptor ligands. 2. High-affinity ligands with selectivity for bone cell progesterone receptors.
A novel series of nonsteroidal heterocycles was discovered which display cell-type selective, high-affinity (nanomolar) binding to the progesterone receptors from TE85 osteosarcoma cells but > 1 microM binding affinity to the progesterone receptors from T47D and ZR75 human breast carcinoma cells. Structure-activity relationships were developed for a set of these compounds, and a representative analog 1-(3,4-dichlorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine++ + (1i, RWJ 25333) was chosen for further evaluation. RWJ 25333 stimulated the in vitro proliferation of human osteoblast-like cells but not human breast cells.
R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869-0602, USA.
D W
DW
Combs
K
K
Reese
L A
LA
Cornelius
J W
JW
Gunnet
E V
EV
Cryan
K S
KS
Granger
J J
JJ
Jordan
K T
KT
Demarest
D001859:Bone Neoplasms; D001842:Bone and Bones / Q000378:metabolism*; D001943:Breast Neoplasms; D015195:Drug Design; D005260:Female; D006801:Humans; D008024:Ligands; D011372:Progestins / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D008024:Ligands; D011372:Progestins; D011724:Pyridazines; C097233:RWJ 25333; D011980:Receptors, Progesterone