Preclinical pharmacokinetic investigation of the bioavailability and skin distribution of HY-072808 ointment, a novel drug candidate for the treatment of atopic dermatitis, in minipigs by a newly LC-MS/MS method.

HY-072808 is a novel phosphodiesterase 4 inhibitor clinically used for topical atopic dermatitis treatment. Cytochrome P450 enzymes are involved in transforming it into major metabolite ZZ-24. An efficient UPLC-MS/MS method was established to detect HY-072808 and ZZ-24 in plasma and skin tissues of minipigs.One-step protein precipitation was performed with acetonitrile. Subsequently, elution was served with a methanol and water gradient containing 0.1% formic acid for 3.5 min. The plasma and skin tissue concentrations of HY-072808 and ZZ-24 showed good linearity from 0.200 to 200 ng/mL.The experimental minipigs exhibited low systemic exposure and bioavailability of 3.1-7.6% after transdermal application of 1-4% HY-072808 ointment. Multiple topical administrations over seven consecutive days showed a minor accumulation in systemic exposure, with accumulation factors of 2.3 and 4.0 for HY-072808 and ZZ-24, respectively.The distribution of HY-072808 ointment among different cortical layers in minipigs was studied for the first time. Following transdermal application of 2% HY-072808 ointment, the concentration in plasma and skin tissues in the order of epidermis > dermis > subcutaneous tissue ≈ subcutaneous muscle ≈ plasma; at 48 h after the administration, the epidermis and dermis still had a high concentration of the drug.

Design, Synthesis, and Biological Evaluation of Pierardine Derivatives as Novel Brain-Penetrant and In Vivo Potent NMDAR-GluN2B Antagonists for Ischemic Stroke Treatment.

A series of structurally novel GluN2B NMDAR antagonists were designed, synthesized, and biologically evaluated as anti-stroke therapeutics by optimizing the chemical structure of Pierardine, the active ingredient of traditional Chinese medicine Dendrobium aphyllum (Roxb.) C. E. Fischer identified via in silico screening. The systematic structure-activity relationship study led to the discovery of 58 with promising NMDAR-GluN2B binding affinity and antagonistic activity. Of the two enantiomers, S-58 exhibited significant inhibition (IC50 = 74.01 ± 12.03 nM) against a GluN1/GluN2B receptor-mediated current in a patch clamp assay. In addition, it displayed favorable specificity over other subtypes and off-target receptors. In vivo, S-58 exerted therapeutic efficacy comparable to that of the approved GluN2B NMDAR antagonist ifenprodil and excellent safety profiles. In addition to the attractive in vitro and in vivo potency, S-58 exhibited excellent brain exposure. In light of these merits, S-58 has been advanced to further preclinical investigation as a potential anti-stroke candidate.

Discovery of the novel and potent histamine H1 receptor antagonists for treatment of allergic diseases.

Desloratadine, a second-generation histamine H1 receptor antagonist, has established itself as a first-line drug for the treatment of allergic diseases. Despite its effectiveness, desloratadine exhibits an antagonistic effect on muscarinic M3 receptor, which can cause side effects such as dry mouth and urinary retention, ultimately limiting its clinical application. Herein, we describe the discovery of compound Ⅲ-4, a novel H1 receptor antagonist with significant H1 receptor antagonistic activity (IC50 = 24.12 nM) and enhanced selectivity towards peripheral H1 receptor. In particular, Ⅲ-4 exhibits reduced M3 receptor inhibitory potency (IC50 > 10,000 nM) and acceptable hERG inhibitory activity (17.6 ± 2.1 µM) compare with desloratadine. Additionally, Ⅲ-4 exhibits favorable pharmacokinetic properties, as well as in vivo efficacy and safety profiles. All of these reveal that Ⅲ-4 has potential to emerge as a novel H1 receptor antagonist for the treatment of allergic diseases. More importantly, the compound Ⅲ-4 (HY-078020) has recently been granted clinical approval.