title: 5-Aryl-1,2,3,4-tetrahydrochromeno[3,4-f]quinolin-3-ones as a novel class of nonsteroidal progesterone receptor agonists: effect of A-ring modification.
abstract: Optimization of the 1,2-dihydroquinoline A-ring of a nonsteroidal human progesterone receptor (hPR) agonist pharmacophore (1) was performed by using the cotransfection and receptor binding assays as guides. The 3-keto group was discovered to regain the potent agonist activity which was lost upon removal of the 3,4-olefin, and it led to a novel hPR agonist series, 5-aryl-1,2,3,4-tetrahydrochromeno[3, 4-f]quinolin-3-ones. The new progestins demonstrated potent hPR agonist activity in the cotransfection assay and high binding affinity similar to progesterone. T47D human breast cancer cell line was employed for further characterization of the new progestins and a number of reference analogues. It was found that the new 3-keto analogues showed full agonist activity in the T47D assay, while the reference compounds from other related nonsteroidal hPR agonist series exhibited only partial agonist activity.
authors.affiliation: Departments of Medicinal Chemistry, New Leads Discovery, and Endocrine Research, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhi
authors.forename: C M
authors.initials: CM
authors.lastname: Tegley
authors.forename: K B
authors.initials: KB
authors.lastname: Marschke
authors.forename: D E
authors.initials: DE
authors.lastname: Mais
authors.forename: T K
authors.initials: TK
authors.lastname: Jones
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D008024:Ligands; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000819:agonists* / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D008024:Ligands; D015363:Quinolones; D011980:Receptors, Progesterone