Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists: Discovery and Lead Exploration

Abstract

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.

Ruthenium-Catalyzed Alkyne trans-Hydrometalation: Mechanistic Insights and Preparative Implications

“…A closer inspection of the bound alkyne is equally informative. The substantial elongation of the CC bond indicates a high degree of activation which is qualitatively in line with the massive deshielding observed by 13 C NMR. Interestingly, the CC bond in 5 (1.283(1) Å) is longer than that in 4 (1.264(4) Å) and the alkyne slightly more bent away from linearity (C3–C2–C1 144.75(8)° versus 145.3(3)°).…”

2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as Potent Dissociated Glucocorticoid Receptor Agonists

“…10 In our first paper, we described the discovery of a novel series of DAGRs containing the octahydrophenanthrene-2,7-diol pharmacophore (1−5, Table 1). 5 These analogues functioned as agonists in in vitro assays of TR (inhibition of IL-1 induced IL-8 and MMP-13 expression) but possessed reduced capacity for TA in an assay measuring activation of a mouse mammary tumor virus (MMTV) reporter construct, as compared to DEX. In addition, we outlined our early optimization efforts on this series focusing on replacing the allyl (R 4 ) and particularly the propynyl (R 2 ) substituents with those more likely to be chemically stable and less likely to produce toxic metabolites.…”

“…This has led to the discovery of a novel pharmacophore that demonstrated a spectrum of TR/TA activities that differed from those of classical GR agonists. 5 Arguably, compounds displaying such dissociated activities represent potential candidates to test for improved safety/efficacy profiles in human. In fact, a recent phase 2 clinical study with DAGR PF-04171327 has shown similar efficacy to 10 mg of PRED but with effects on bone formation and glucose markers at 5 mg of PRED.…”

Selective Glucocorticoid Receptor modulators

“…Evidence of the clear interest in the field of non-steroidal dissociated GR ligands is provided by the considerable number of compounds reported (reviewed in [60]) that are able to bind GR with a more favorable profile as compared to standard classic GCs. These include Boehringer Ingelheim's BI 115 and Compound 36 [61], GSK's tetrahydronaphthaline-methylbenzoxazinones [62] and arylpyrazoles [63] or a 6,5-bicyclic core fused to a pyrazole ring (Merck) [64], Compound 15 (UCSF), Compound 25 (Merck), or the recently reported Compound 2 (Pfizer) [65]. Data on side effect parameters are still lacking for many of these compounds.…”