5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.
A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.
Tegley
C M
CM
Department of Medicinal Chemistry, New Leads Discovery, and Endocrine Research, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA.
Zhi
L
L
Marschke
K B
KB
Gottardis
M M
MM
Yang
Q
Q
Jones
T K
TK
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects
C115430:1,2-dihydro-5-(2-methylbenzylidene)-2,2,4-trimethyl-5H-chromeno(3,4-f)quinoline; C115429:5-(3-fluorobenzylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno(3,4-f)quinoline; D001578:Benzopyrans; D011804:Quinolines; D011980:Receptors, Progesterone; D011374:Progesterone; D017258:Medroxyprogesterone Acetate