ABSTRACT
A series of 2H-pyrano[3,2-g]quinolin-2-ones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one, displayed moderate interaction with hAR, but substituted analogues were potent hAR modulators in vitro as measured by an hAR cotransfection assay in CV-1 cells and bound to hAR with high affinity in a whole cell assay. Several analogues were able to activate hAR-mediated gene transcription more potently and efficaciously than dihydrotestosterone.
Subject(s)
Androgens , Benzopyrans/chemistry , Benzopyrans/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Animals , COS Cells , Cell Line , Humans , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Structure-Activity Relationship , Transcription, Genetic/drug effects , TransfectionABSTRACT
A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG001447 (1,2-dihydro-2,2, 4-trimethyl-6-phenylquinoline) was discovered via directed high throughput screening of a defined chemical library utilizing an hPR-B cotransfection assay. Electron-withdrawing substituents at the meta position of the C(6) aryl group afforded substantial improvements in hPR modulatory activity. Several analogues were able to potently block the effects of progesterone in vitro. Two compounds, 10 (LG120753) and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral administration to rodents. This is the first disclosure of orally active nonsteroidal antiprogestins.
Subject(s)
Hormone Antagonists , Quinolines , Receptors, Progesterone/antagonists & inhibitors , Administration, Oral , Animals , Cell Line , Cercopithecus , Embryo Implantation/drug effects , Female , Gonanes/pharmacology , Hormone Antagonists/administration & dosage , Hormone Antagonists/chemical synthesis , Hormone Antagonists/chemistry , Hormone Antagonists/pharmacology , Humans , Mice , Pregnancy , Quinolines/administration & dosage , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Progesterone/biosynthesis , Structure-Activity RelationshipABSTRACT
Two potent nonsteroidal progestins from the 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinoline class (LG120746 and LG120747) were selected for scale-up, resolution, and biological evaluation of the purified enantiomers. For each quinoline, the levorotatory enantiomer was determined to be the more potent agonist of the human progesterone receptor isoform B (hPR-B) (EC50 < 3 nM), but the dextrorotatory enantiomers retained significant PR modulatory activity (EC50 < 200 nM). In two in vivo rodent models of progestational activity, a pregnancy maintenance assay and a uterine wet weight assay, the two eutomers displayed potent progesterone-like effects. In a third model for progestational activity, the mammary end bud assay, these compounds were significantly less active. These studies demonstrate that certain members of this class of selective progesterone receptor modulators display encouraging and potentially useful tissue-selective progestational effects.
Subject(s)
Benzopyrans , Quinolines , Receptors, Progesterone/agonists , Administration, Oral , Animals , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Benzopyrans/isolation & purification , Benzopyrans/pharmacology , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Embryo Implantation/drug effects , Female , Humans , Mammary Glands, Animal/cytology , Mammary Glands, Animal/drug effects , Mice , Mice, Inbred ICR , Mitosis/drug effects , Molecular Conformation , Organ Size/drug effects , Ovariectomy , Pregnancy , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/isolation & purification , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Progesterone/metabolism , Stereoisomerism , Uterus/drug effects , Uterus/growth & developmentABSTRACT
A series of 2(1H)-pyrrolidino[3,2-g]quinolinones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinone, displayed moderate interaction with hAR, but more substituted analogues, particularly 6,7-disubstituted compounds, were potent hAR agonists in vitro.
Subject(s)
Androgen Antagonists/pharmacology , Pyrrolidines/pharmacology , Quinolines/pharmacology , Quinolones/pharmacology , Receptors, Androgen/genetics , Transcription, Genetic/drug effects , Androgen Antagonists/chemical synthesis , Androgen Antagonists/chemistry , Anilides/chemistry , Anilides/pharmacology , Animals , Cell Line , Drug Design , Flutamide/chemistry , Flutamide/pharmacology , Gene Expression Regulation/drug effects , Humans , Molecular Structure , Nitriles , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolones/chemical synthesis , Quinolones/chemistry , Recombinant Proteins/biosynthesis , Structure-Activity Relationship , Tosyl Compounds , TransfectionABSTRACT
A series of nonsteroidal human progesterone receptor (hPR) antagonists based on conformationally-restricted analogues of a 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline pharmacophore were synthesized and evaluated for their ability to bind to the human progesterone receptor and inhibit progesterone-stimulated reporter gene expression in mammalian cells.
