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.

Synthesis and biological evaluation of N-(benzene sulfonyl)acetamide derivatives as anti-inflammatory and analgesic agents with COX-2/5-LOX/TRPV1 multifunctional inhibitory activity.

In this study, a series of structurally novel N-(benzene sulfonyl) acetamide derivatives were designed, synthesized, and biologically evaluated as COX-2/5-LOX/TRPV1 multitarget inhibitors for anti-inflammatory and analgesic therapy. Among them, 9a and 9b displayed favorable COX-2 (9a IC50 = 0.011 µM, 9b IC50 = 0.023 µM), 5-LOX (9a IC50 = 0.046 µM, 9b IC50 = 0.31 µM) and TRPV1 (9a IC50 = 0.008 µM, 9b IC50 = 0.14 µM) inhibitory activities. The pharmacokinetic (PK) study of 9a in SD rats at the dosage of 10 mg/kg demonstrated a high oral exposure, an acceptable clearance and a favorable bioavailability (Cmax = 5807.18 ± 2657.83 ng/mL, CL = 3.24 ± 1.47 mL/min/kg, F = 96.8 %). Further in vivo efficacy studies illustrated that 9a was capable of ameliorating formalin-induced pain and inhibiting capsaicin-induced ear edema.

Discovery of novel brain-penetrant GluN2B NMDAR antagonists via pharmacophore-merging strategy as anti-stroke therapeutic agents.

In this work, a novel structural series of brain-penetrant GluN2B NMDAR antagonists were designed, synthesized and biologically evaluated as anti-stroke therapeutic agents via merging the structures of NBP and known GluN2B ligands. Approximately half of them exhibited superior neuroprotective activity to NBP against NMDA-induced neurotoxicity in hippocampal neurons at 10 µM, and compound 45e and 45f exerted equipotent activity to ifenprodil, an approved GluN2B- selective NMDAR antagonist. In particular, 45e, with the most potent neuroprotective activity throughout this series, displayed dramatically enhanced activity (Ki = 3.26 nM) compared to ifenprodil (Ki = 14.80 nM) in Radioligand Competitive Binding Assay, and remarkable inhibition (IC50 = 79.32 nM) against GluN1/GluN2B receptor-mediated current in Patch Clamp Assay. Meanwhile, 45e and its enantiomers exhibited low inhibition rate against the current mediated by other investigated receptors at the concentration of 10 µM, indicating their favorable selectivity for GluN1/GluN2B. In the rat model of middle cerebral artery ischemia (MCAO), 45e exerted comparable therapeutic efficacy to ifenprodil at the same dosage. In addition to the attractive in vitro and in vivo potency, 45e displayed a favorable bioavailability (F = 63.37%) and an excellent brain exposure. In further repeated dose toxicity experiments, compound 45e demonstrated an acceptable safety profile. With the above merits, 45e is worthy of further functional investigation as a novel anti-stroke therapeutic agent.

Design, synthesis and biological evaluation of novel benzoxaborole derivatives as potent PDE4 inhibitors for topical treatment of atopic dermatitis.

In this work, a series of structurally novel benzoxaborole derivatives were designed, synthesized and biologically evaluated as PDE4 inhibitors for battling atopic dermatitis (AD). Among them, the majority exhibited superior PDE4B inhibitory activities to that of the lead compound Crisaborole, an approved PDE4 inhibitor. In particular, 72, the most potent PDE4B inhibitor throughout this series, displayed 136-fold improved enzymatic activity (IC50 = 0.42 nM) as compared to Crisaborole (IC50 = 57.20 nM), along with favorable isoform specificity. In the phorbol ester (PMA)-induced mouse ear oedema model, 72 exerted remarkably greater efficacy than Crisaborole at the same dosage (P < 0.05). Moreover, the ointment of 72 exerted dramatically enhanced therapeutic potency than the ointment of Crisaborole (P < 0.05) in the calcipotriol-induced mouse AD model. In addition to the potent in vitro and in vivo activity, 72 displayed favorable safety in the repeated oral dose toxicity study and did not exhibit phototoxicity. With the above attractive biological performance, 72 is worthy of further functional investigation as a novel anti-AD therapeutic agent.

Design, synthesis and biological evaluation of novel desloratadine derivatives with anti-inflammatory and H1 antagonize activities.

To improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H1 antagonistic activities. Among them, compound 2c showed the strongest H1 antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.

Design, synthesis chalcone derivatives as AdipoR agonist for type 2 diabetes.

Two structurally novel series of chalcone derivatives were designed and synthesized as potential agents against type 2 diabetes. As a result of the antidiabetic biological evaluation in streptozotocin (STZ)-induced type 2 diabetes animal model, 13e, 13g, and 19f showed more significant reduction in serum Glu, TG, TC levels by contrast to the positive control AdipoRon. In addition to upregulating the expression of AdipoR1 and AdipoR2, 13e and 19f treatment also increased expression of AMPK and PPAR-α. Taken together, these results suggested that 13e and 19f might be a promising compound for type 2 diabetes treatment.

Synthesis and evaluation of salicylanilide derivatives as potential epidermal growth factor receptor inhibitors.

Two series of novel salicylanilide were synthesized as potential epidermal growth factor receptor (EGFR) inhibitors. The enzyme inhibitory activity against EGFR of all compounds was carried out, and their antiproliferative activities against the A549 and A431 cell lines were also evaluated. Of the compounds studied, majority of them exhibited high antiproliferative activities compared with gefitinib; especially, 12a and 12b exhibited stronger inhibitory activity against EGFR with IC50 values of 10.4 ± 2.25 and 15.4 ± 2.33 nm, respectively, which were comparable to the positive control of gefitinib (IC50 = 12.1 ± 2.21 nm). Compound 12b also showed outstanding inhibitory activity against A431 and A549 cell lines with the IC50 values of 0.42 ± 0.43 µm and 0.57 ± 0.43 µm, which was better than the positive controls. In the molecular modeling study, compound 12b was bound into the active pocket of EGFR with two hydrogen bond and with minimum binding free energy ▵Gb = -25.1125 kcal/mol. The result also suggested that compound 12b could bind the EGFR kinase well.