Jeffrey Curtis Kern

Design, Synthesis, and SAR of New Pyrrole-Oxindole Progesterone Receptor Modulators Leading to 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348)

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.

A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation

Canonical Wnt signaling has been demonstrated to increase bone formation, and Wnt pathway components are being pursued as potential drug targets for osteoporosis and other metabolic bone diseases. Deletion of the Wnt antagonist secreted frizzled-related protein (sFRP)-1 in mice activates canonical signaling in bone and increases trabecular bone formation in aged animals. We have developed small molecules that bind to and inhibit sFRP-1 in vitro and demonstrate robust anabolic activity in an ex vivo organ culture assay. A library of over 440,000 drug-like compounds was screened for inhibitors of human sFRP-1 using a cell-based functional assay that measured activation of canonical Wnt signaling with an optimized T-cell factor (TCF)-luciferase reporter gene assay. One of the hits in this screen, a diarylsulfone sulfonamide, bound to sFRP-1 with a K(D) of 0.35 microM in a tryptophan fluorescence quenching assay. This compound also selectively inhibited sFRP-1 with an EC(50) of 3.9 microM in the cell-based functional assay. Optimization of this high throughput screening hit for binding and functional potency as well as metabolic stability and other pharmaceutical properties led to improved lead compounds. One of these leads (WAY-316606) bound to sFRP-1 with a K(D) of 0.08 microM and inhibited it with an EC(50) of 0.65 microM. Moreover, this compound increased total bone area in a murine calvarial organ culture assay at concentrations as low as 0.0001 microM. This work demonstrates the feasibility of developing small molecules that inhibit sFRP-1 and stimulate canonical Wnt signaling to increase bone formation.

Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides.

The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.

7-Aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists

Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC(50) of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.

Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides: Part II

Piperidinyl diphenylsulfonyl sulfonamides are a novel class of molecules that have inhibitory binding affinity for sFRP-1. As a secreted protein sFRP-1 inhibits the function of the secreted Wnt glycoprotein. Therefore, as inhibitors of sFRP-1 these small molecules facilitate the Wnt/beta-catenin canonical signaling pathway. Details of the structure-activity relationships and biological activity of this structural class of compounds will be discussed.

Synthesis and evaluation of azabicyclo[3.2.1]octane derivatives as potent mixed vasopressin antagonists

A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V(1a)- and good V(2)-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the programs mixed V(1a)/V(2)-receptor antagonist standard.

1-Methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalene derivatives as non-steroidal progesterone receptor antagonists

Non-steroidal 1-methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalenes and acyclic derivatives were evaluated as novel series of progesterone receptor (PR) antagonists using the T47D cell alkaline phosphatase assay. Moderate to potent PR antagonists were achieved with these scaffolds. Several compounds (e.g., 15 and 20) demonstrated low nanomolar PR antagonist potency and good selectivity versus other steroid receptors.

5-Aryl indanones and derivatives as non-steroidal progesterone receptor modulators.

Novel 5-aryl indanones, inden-1-one oximes, and inden-1-ols were synthesized and evaluated as progesterone receptor (PR) modulators using the T47D cell alkaline phosphatase assay. Both PR agonists and antagonists were achieved with appropriate 3- and 5-substitution from indanones and inden-1-ols while inden-1-one oximes provided only PR antagonists. Several compounds such as 10 and 11 demonstrated potent in vitro PR agonist potency similar to that of steroidal progesterone (1). In addition, a number of compounds (e.g., 12, 13, 17, 18) showed potent PR antagonist activity indicating the indanones and derivatives are promising PR modulator templates.

3-(Pyridin-2-yl-ethynyl)benzamide metabotropic glutamate receptor 5 negative allosteric modulators: hit to lead studies.

A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC(50): 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s<50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K(i): 21 nM) and antagonism (IC(50): 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk).