Computational Insights into Novel Inhibitor N-(3-(tert-Butylcarbamoyl)-4-methoxyphenyl)-indole and Ingliforib Specific against GP Isoenzyme Dimers Interaction Mechanism.

Article

作者: Zhang, Liying ; Yan, Zhiwei ; Li, Shuai ; Wang, Youde

The high conservation of the three subtypes of glycogen phosphorylase (GP) presents significant challenges for specific inhibitor studies targeting GP. Our prior screening revealed that compound 1 exhibited unequal inhibitory activity against the three GP subtypes, with a noticeable effect against brain GP (PYGB). The commercially available ingliforib demonstrated potent inhibitory activity specifically against liver GP (PYGL). To guide the further design and screening of high-specificity inhibitors, the possible reasons for the differential inhibitory activity of two compounds against different GP subtypes were analyzed, with ingliforib as a reference, through molecular docking and molecular dynamics simulations. Initially, the study predicted the binding modes of ligands with the three GP receptor subtypes using molecular docking. Subsequently, this was validated by molecular dynamics experiments, and possible amino acid residues that had important interactions were explored. The strong correlation between the calculated interaction free energies and experimental inhibitory activity implied the reasonable binding conformations of the compounds. These findings offer insight into the different inhibitory activity of compound 1 and ingliforib against all three GP subtypes and provide guidance for the design of specific target molecules that regulate subtype selectivity.

2022-12-01·Bioorganic Chemistry

Discovery of novel heterocyclic derivatives as potential glycogen phosphorylase inhibitors with a cardioprotective effect

Article

作者: Yan, Zhiwei ; Li, Jing ; Ma, Can ; Li, Shuai ; Wang, Youde ; Zhang, Liying ; Guo, Yachun

The purpose of this study was to evaluate the effect of GP inhibitor as a potential pharmaceutical target on MI/R injury. Four different structural types of novel compounds (I, II, III, and IV) were designed and synthesized, obtaining 31 novel GP inhibitors. SAR studies revealed that the conjugates of 5-chloroindole with benzo six-membered heterocyclic were found to elevate the activity. In particular, compound IIIh (IC₅₀ = 0.21 ± 0.03 µM) emerged as a potent derivative against RMGPa, being approximately 2-fold less potent than that of PSN-357. In order to screen out a compound for in vivo activity test, we further conducted an experiment of inhibition against three different subtypes of GPa (HLGPa, HMGPa and HBGPa) and the corresponding affinity experiment. As a result, compound IIIh showed strong inhibitory activity against the above three subtypes of GP, especially on HBGPa (IC₅₀ = 0.09 ± 0.002 µM), which was relatively close to that of positive control ingliforib (IC₅₀ = 0.16 ± 0.02 µM). The affinity of compound IIIh to HBGPa was 4.3 times higher than that of HLGPa, and 1.1 times higher than that of HMGPa. This fact further proved that compound IIIh has a higher inhibitory effect on HMGPa than the other two subtypes. Besides, in vivo activity evaluation demonstrated that compound IIIh exhibited obviously cardioprotective effect on MI/R injury mice. The discovery of compound IIIh provides a new strategy for developing novel GP inhibitors with myocardial ischemia protection.

2013-07-01·Journal of Controlled Release1区 · 医学

Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs

1区 · 医学

Article

作者: John Litchfield ; Graeme Taylor ; Manthena Varma ; Paul Nkansah ; Ying Lu ; Ayman El-Kattan ; Mario Rubio ; Charles Rotter ; Brian Rago ; Amy Antipas

The aim of the present study was to develop and evaluate a novel drug solubilization platform (so-called solid nanodispersion) prepared by a simple co-grinding and solvent-free process. Using structurally diverse model compounds from the Pfizer drug library, including ingliforib, furosemide and celecoxib, we successfully prepared stable solid nanodispersions (SNDs) without the use of solvent or heat. Stable colloidal particles (<350 nm) containing drug, polyvinylpyrrolidone (PVP) K12 and sodium dodecyl sulfate (SDS) in 1:2.75:0.25 ratio were produced after 2 h of co-grinding. The composition and particle size of SNDs were optimized by varying the grinding media size, powder-to-grinding media ratio, milling speed and milling time. The resulting formulations contained crystalline drug and were stable at room temperature for over one month. Greater than 80% of the drug was released from the SND in less than 30 min, with sustained supersaturation over 4 h. Using furosemide (BCS class IV compound) as a model compound, we conducted transport studies with Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK/MDR1), followed by pharmacokinetics studies in rats. Results showed that the SND formulation enhanced the absorptive flux of furosemide by more than 3-fold. In the pharmacokinetics studies, the SND formulation increased C(max) and AUC of furosemide by 36.6 and 43.2 fold respectively, relative to Methocel formulation. Interestingly, physical mixture containing furosemide, PVP K12 and SDS produced a similar level of oral exposure as the SNDs, albeit with a longer T(max) than the SND formulation. The results suggest that PVP K12 and SDS were able to increase the furosemide free fraction available for oral absorption. Low solubility, poor permeability, and high first-pass effect of furosemide may also have produced the effect that small improvements in solubilization resulted in significant potentiation of the oral exposure of the physical mixture. However the use of a physical mixture of drug, polymer and surfactant, to increase drug bioavailability cannot be generalized to all drugs. There are only a few reported cases of such phenomenon. While SNDs may not be the only option to solubilize compounds in every case, SNDs are expected to be applicable to a broader chemical space of pharmaceutical compounds compared to a physical mixture. Ultimately, the formulation scientist will have to exercise judgment in choosing the appropriate formulation strategy for the compound of interest. SNDs represent a significant improvement over current enabling technologies such as nanocrystal and spray-dried dispersion technologies, in that SNDs are simple, do not require solvent or heat, are applicable to a structurally diverse chemical space, and are readily amenable to the development of solid dosage forms.

100 项与 Ingliforib 相关的药物交易

登录后查看更多信息