Ingliforib

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.

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.