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)

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.

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…Of the novel class of cyanophenoxypyrazoles, PF-02367982 dose-dependently inhibited the progesterone-mediated aborisation of the endometrium and delayed menses induction when dosed for 20 days from the start of the menstrual cycle. PF-02367982 also increased AR protein expression in a similar manner to that observed by RU-486 and the non-steroidal PRA, WAY-255348 (de Giorgio-Miller et al, 2008;Fensome et al, 2008). These data are consistent with other non-steroidal PRAs that have been assessed, such as WAY-255348 (Fensome et al, 2008).…”

“…PF-02367982 also increased AR protein expression in a similar manner to that observed by RU-486 and the non-steroidal PRA, WAY-255348 (de Giorgio-Miller et al, 2008;Fensome et al, 2008). These data are consistent with other non-steroidal PRAs that have been assessed, such as WAY-255348 (Fensome et al, 2008). More recently, PF-02413873 a more potent PRA than PF-02367982 (Table 1) has been shown to reduce endometrial cell proliferation and thickness in intact macaques dosed for 10 days from the start of menstruation (Howe et al, 2011).…”

“…These might have advantages over the steroidal templates due to simpler synthetic route, and potential for greater selectivity and metabolic stability compared with steroidal templates (Dack et al, 2010;Fensome et al, 2008;Terefenko et al, 2005;Zhang et al, 2002),. With a few exceptions, these classes of agents tend to mimic the steroid A ring ketone with a cyanoaryl group isostere, as is also seen with tanaproget, the non-steroidal progestogen .…”

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

“…The broader clinical utility of RU-486 as a new approach to the treatment of endometriosis, uterine fibroids, and dysfunctional uterine bleeding, for instance, is limited because of antagonism at the glucocorticoid receptor (GR) (Heikinheimo et al, 1987) and effects on corticotropin secretion. Consequently, there has been considerable medicinal chemistry investment focused on identifying alternative chemical equity that has greater selectivity for PR over GR as well as other nuclear hormone receptors (NHRs) (Attardi et al, 2002;Jones et al, 2005;Terefenko et al, 2005;Kern et al, 2007Kern et al, , 2009Kern et al, , 2010Zhang et al, 2007aZhang et al, , 2008Fensome et al, 2008;Dack et al, 2010).…”

Development of Functional Molecules for Elucidation of the Physiological Roles of Several Nuclear Receptors and Their Endogenous Ligands

“…So far, nitrogen-containing heterocycles fused with an arylsubstituted benzene ring, such as compounds 3 and 4, have been widely studied. [43][44][45][46][47] Considering the structures of these non-steroidal PR ligands, we thought that bicyclic 6-arylcoumarin would be an alternative scaffold. Coumarin is one of widely used fluorophore, and the fluorescence properties of its derivatives are known to depend upon the nature and position of substituents.…”