Nonsteroidal progesterone receptor ligands with unprecedented receptor selectivity.
We have characterized a series of nonsteroidal progesterone receptor ligands, the tetrahydropyridazines. Compounds in this series, exemplified by RWJ 26819, demonstrate high affinity and unprecedented specificity for the progesterone receptor relative to other steroid hormone receptors. Like steroidal progestins, RWJ 26819 induces binding of the receptor to a progesterone response element in vitro, and stimulates gene expression in and proliferation of T47D human breast cancer cells. When administered to rabbits orally or subcutaneously, the compound induces histological changes in the uterine lining comparable to those induced by levonorgestrel. It also inhibits ovulation in monkeys. Though less potent in cells and in animal models than would be predicted from binding affinity alone, their enhanced selectivity suggests that they could be effectively used in a clinical setting. Most of the tetrahydropyridazines synthesized are progestin agonists or mixed agonists and antagonists in vitro; however, one compound with antagonist activity in the rabbit uterine transformation assay has been identified.
Palmer
S
S
R.W. Johnson Pharmaceutical Research Institute, 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA.
Campen
C A
CA
Allan
G F
GF
Rybczynski
P
P
Haynes-Johnson
D
D
Hutchins
A
A
Kraft
P
P
Kiddoe
M
M
Lai
M
M
Lombardi
E
E
Pedersen
P
P
Hodgen
G
G
Combs
D W
DW
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D016912:Levonorgestrel / Q000378:metabolism; D008252:Macaca fascicularis; D015735:Mifepristone / Q000378:metabolism; D010060:Ovulation / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D010879:Piperazines; D010880:Piperidines; D011724:Pyridazines; C423502:RWJ 26819; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D015735:Mifepristone; D011374:Progesterone; D016912:Levonorgestrel; D000469:Alkaline Phosphatase