ABSTRACT
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).
Subject(s)
Benzoxazines/pharmacology , Indoles/pharmacology , Pyrroles/chemistry , Receptors, Progesterone/drug effects , Benzoxazines/chemistry , Indoles/chemistryABSTRACT
A new series of 3,3-disubstituted-5-aryloxindoles has been synthesized and evaluated for progesterone receptor antagonist (PR) activity in a T47D cell alkaline phosphatase assay and for their ability to bind PR in competition binding studies. In this communication, the synthesis and structure-activity relationships (SARs) of various 3,3-substituents are discussed where it is clear that small alkyl and spiroalkyl groups are required to achieve better PR antagonist activity.
