ABSTRACT
We have continued to explore the 3,3-dialkyl-5-aryloxindole series of progesterone receptor (PR) modulators looking for new agents to be used in female healthcare: contraception, fibroids, endometriosis, and certain breast cancers. Previously we reported that subtle structural changes with this and related templates produced functional switches between agonist and antagonist properties ( Fensome et al. Biorg. Med. Chem. Lett. 2002, 12, 3487; 2003, 13, 1317 ). We herein report a new functional switch within the 5-(2-oxoindolin-5-yl)-1 H-pyrrole-2-carbonitrile class of compounds. We found that the size of the 3,3-dialkyl substituent is important for controlling the functional response; thus small groups (dimethyl) afford potent PR antagonists, whereas larger groups (spirocyclohexyl) are PR agonists. The product from our optimization activities in cell-based systems and also for kinetic properties in rodents and nonhuman primates was 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-1-methyl-1 H-pyrrole-2-carbonitrile 27 (WAY-255348), which demonstrated potent and robust activity on PR antagonist and contraceptive end points in the rat and also in cynomolgus and rhesus monkeys including ovulation inhibition, menses induction, and reproductive tract morphology.
Subject(s)
Drug Design , Indoles/chemistry , Indoles/chemical synthesis , Indoles/pharmacology , Pyrroles/chemistry , Receptors, Progesterone/antagonists & inhibitors , Administration, Oral , Alkaline Phosphatase/drug effects , Animals , Dose-Response Relationship, Drug , Female , Humans , Macaca fascicularis , Macaca mulatta , Molecular Structure , Ovulation/drug effects , Oxindoles , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Rats , Receptors, Progesterone/chemistry , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.
Subject(s)
Benzoxazines/chemical synthesis , Oxazines/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Progesterone/agonists , Thiones/chemical synthesis , Alkaline Phosphatase/metabolism , Animals , Area Under Curve , Benzoxazines/chemistry , Benzoxazines/pharmacology , Binding, Competitive , Cell Line, Tumor , Contraceptive Agents, Female/chemical synthesis , Contraceptive Agents, Female/chemistry , Contraceptive Agents, Female/pharmacology , Decidua/drug effects , Decidua/metabolism , Female , Half-Life , Humans , In Vitro Techniques , Ligands , Molecular Structure , Oxazines/chemistry , Oxazines/pharmacology , Protein Structure, Tertiary , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Progesterone/antagonists & inhibitors , Receptors, Progesterone/chemistry , Structure-Activity Relationship , Thiones/chemistry , Thiones/pharmacologyABSTRACT
A series of 1,4-dihydro-2H-[d][3,1]-benzoxazin-2-one and 1,3-dihydro-[3H]-indol-2-one containing 6- or 5-, respectively, appended substituted pyrrole moieties were synthesized and evaluated for their ability to modulate the activity of the progesterone receptor (PR). Key structural changes to the pyrrole moieties of these molecules were shown to have a predictive influence as to whether the compounds behaved as PR agonists or antagonists. Compounds with the 5(')-cyano-2(')-pyrrole moiety (e.g., 32, 33, and 38) were shown to be potent PR agonists (EC(50)'s of 1.1, 1.8, and 2.8 nM, respectively). Compounds with the 5(')-nitro-2(')-pyrrole moiety (e.g., 34 and 36) were shown to be PR antagonists (IC(50)'s of 180 and 36 nM, respectively).
