3-Alkoxy-pyrrolo[1,2-b]pyrazolines as Selective Androgen Receptor Modulators with Ideal Physicochemical Properties for Transdermal Administration

Abstract

We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed high aqueous solubility of 1.3 g/L at pH 7.4, and an in silico model as well as a customized parallel artificial membrane permeability assay indicated good skin permeation. Indeed, when measuring skin permeation through excised human skin, an excellent flux of 2 μg/(cm(2)·h) was determined without any permeation enhancers. In a 2 week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation.

Predictive Structure-Based Toxicology Approaches To Assess the Androgenic Potential of Chemicals

“…Docking simulations were conducted using nine AR crystal structures retrieved from the Protein Data Bank (PDB) (Berman et al, 2000) selected as follows: six crystal structures previously selected by Kolšek et al (2014) based on their capability to provide highly predictive docking-based classification models, and two of the most recent AR X-ray solved crystals available in the PDB (PDB IDs: 5CJ6 (Saeed et al, 2016) and 4QL8 (Ullrich et al, 2014)). In addition, a crystal structure (PDB ID: 2HVC (Wang et al, 2006)) showing a noncanonical binding mode of the cognate ligand compared to the other selected X-ray complexes was selected.…”

Axially Chiral Cyclic Diphosphine Ligand-Enabled Palladium-Catalyzed Intramolecular Asymmetric Hydroarylation

“…Compounds containing a l,8-diazabicyclo[3.3.0]octane skeleton exhibit diverse biological activities. For example, they are used as the androgen receptor modulator ( Ullrich et al., 2014 ), angiotensin II receptor antagonist ( Levin et al., 1994 ), and DNA topoisomerase inhibitor ( Figure 1 ) ( Katayama et al., 1999 ). However, 1 H -pyrazolo[5,1- a ]isoindol-2(8 H )-ones as their derivatives have been ignored ( Ivanovich et al., 2016 ).…”

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis

“…[16] Finally,g ood skin penetration requires ab alance of properties, that is,l ow molecular weight and aw ell-balanced logD. [17,18] It was clear that these sulfonamide chemotypes could deliver potent RORg inverse agonists, albeit with somewhat high lipophilicity.B ecause high lipophilicity is also often linked to high tissue binding and promiscuity,w ed ecided to investigate bicyclic heteroaromatic sulfonamides as aw ay to potentially offer new templates with reduced lipophilicity. [19] Results and Discussion Synthesis The first strategy started from 4-ethylaniline (19).…”

“…A fast turnover in hepatocytes is also a desired for locally acting topical compounds to ensure low systemic exposure and minimal side effects . Finally, good skin penetration requires a balance of properties, that is, low molecular weight and a well‐balanced log D . It was clear that these sulfonamide chemotypes could deliver potent RORγ inverse agonists, albeit with somewhat high lipophilicity.…”