Discovery of a highly potent glucocorticoid for asthma treatment

Abstract

Glucocorticoids are the most effective treatment for asthma. However, their clinical applications are limited by low efficacy in severe asthma and by undesired side effects associated with high dose or prolonged use. The most successful approach to overcome these limitations has been the development of highly potent glucocorticoids that can be delivered to the lungs by inhalation to achieve local efficacy with minimal systemic effects. On the basis of our previous structural studies, we designed and developed a highly potent glucocorticoid, VSGC12, which showed an improved anti-inflammation activity in both cell-based reporter assays and cytokine inhibition experiments, as well as in a gene expression profiling of mouse macrophage RAW264.7 cells. In a mouse asthma model, VSGC12 delivered a higher efficacy than fluticasone furoate, a leading clinical compound, in many categories including histology and the number of differentiated immune cells. VSGC12 also showed a higher potency than fluticasone furoate in repressing most asthma symptoms. Finally, VSGC12 showed a better side effect profile than fluticasone furoate at their respective effective doses, including better insulin response and less bone loss in an animal model. The excellent therapeutic and side effect properties of VSGC12 provide a promising perspective for developing this potent glucocorticoid as a new effective drug for asthma.

Development of highly potent glucocorticoids for steroid-resistant severe asthma

“…Pathway analysis of the common genes regulated by VSG158, VSG159, FF, and DEX show that the top repressed pathway is the cytokine-cytokine receptor interaction pathway (Kegg pathway # 04060) and the top induced pathway is pyrimidine metabolism (Kegg pathway # 00240) (SI Appendix, Table S1). This is consistent with our previous analysis of VSGC12 (14). Since the cytokine-cytokine receptor interaction is the key pathway that regulates the cellular inflammatory response (21), and its repression is the major target for antiinflammatory effects, we further examined the details of the repression activity on this pathway.…”

“…The low oral bioavailability is due mainly to first-pass hepatic metabolism by the hydrolysis of the S-fluoromethyl carbothioate group from the C-21 position of FP. Previously, we generated VSGC12 based on additional structural clues on the C-6, C-9, and C16 positions of the GC backbone (14). VSGC12 shows a higher potency than FF by i.p.…”

“…In a mouse asthma model, VSGC12 shows a higher potency than intraperitoneally (i.p.) delivered FF and is able to provide the same treatment effect as FF at a dose that does not elicit significant side effects (14). Since high potency has been implicated in improving symptoms of severe asthma, we have further optimized VSGC12 in an attempt to reach the maximal potency for lung inflammation repression and lowering the systemic availability.…”

Channel Expansion in the Ligand-Binding Domain of the Glucocorticoid Receptor Contributes to the Activity of Highly Potent Glucocorticoid Analogues

“…PN4 displayed the exact same interactions but with three additional hydrophobic interactions. The furoyl group present in FF, DX4, and PN4 expanded the LBP and occupied the hydrophobic cavity, as previously described in the literature [16]. Furthermore, the interaction with Asn564 changed from hydrophobic to polar with PN4.…”

“…Interestingly, further modification of this compound through esterification of C-17 with 2-furoyl chloride decreased selectivity due to enhanced TA. This result was expected as furoate ester has proven to dramatically increase potency of several GCs used in treating asthma such as fluticasone furoate (FF), mometasone furoate (MF), and drug candidates such as VSGC12 [16]. Specifically, VSGC12 induced TR activity at one-fourth the concentration of FF while reducing insulin resistance.…”