A Cyclic Phosphoramidate Prodrug of 2'-Deoxy-2'-Fluoro-2'-C-Methylguanosine for the Treatment of Dengue Virus Infection.

Monophosphate prodrug analogs of 2'-deoxy-2'-fluoro-2'-C-methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue virus activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are among the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2'-deoxy-2'-fluoro-2'-C-methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration. We identified a cyclic phosphoramidate, prodrug 17, demonstrating well-balanced anti-dengue virus cellular activity and in vitro stability profiles. We further determined the PBMC concentration of active triphosphate needed to inhibit virus replication by 50% (TP50). Compound 17 was assessed in an AG129 mouse model and demonstrated 1.6- and 2.2-log viremia reductions at 100 and 300 mg/kg twice a day (BID), respectively. At 100 mg/kg BID, the terminal triphosphate concentration in PBMCs exceeded the TP50 value, demonstrating TP50 as the target exposure for efficacy. In dogs, oral administration of compound 17 resulted in high PBMC triphosphate levels, exceeding the TP50 at 10 mg/kg. Unfortunately, 2-week dog toxicity studies at 30, 100, and 300 mg/kg/day showed that "no observed adverse effect level" (NOAEL) could not be achieved due to pulmonary inflammation and hemorrhage. The preclinical safety results suspended further development of compound 17. Nevertheless, present work has proven the concept that an efficacious monophosphate nucleoside prodrug could be developed for the potential treatment of dengue virus infection.

Co-Amorphous Formation of High-Dose Zwitterionic Compounds with Amino Acids To Improve Solubility and Enable Parenteral Delivery.

Solubilization of parenteral drugs is a high unmet need in both preclinical and clinical drug development. Recently, co-amorphous drug formulation has emerged as a new strategy to solubilize orally dosed drugs. The aim of the present study is to explore the feasibility of using the co-amorphous strategy to enable the dosing of parenteral zwitterionic drugs at a high concentration. A new screening procedure was established with solubility as the indicator for co-amorphous co-former selection, and lyophilization was established as the method for co-amorphous formulation preparation. Various amino acids were screened, and tryptophan was found to be the most powerful in improving the solubility of ofloxacin when lyophilized with ofloxacin at a 1:1 weight ratio, with more than 10 times solubility increase. X-ray powder diffraction showed complete amorphization of both components, and an elevated Tg compared with the theoretical value was observed in differential scanning calorimetry. Fourier transform infrared spectroscopy revealed that hydrogen bonding and π-π stacking were possibly involved in the formation of a co-amorphous system in the solid state. Further solution-state characterization revealed the involvement of ionic interactions and π-π stacking in maintaining a high concentration of ofloxacin in solution. Furthermore, co-amorphous ofloxacin/tryptophan at 1:1 weight ratio was both physically and chemically stable for at least 2 months at 40 °C/75% RH. Lastly, the same screening procedure was validated with two more zwitterionic compounds, showing its promise as a routine screening methodology to solubilize and enable the parenteral delivery of zwitterionic compounds.

Novel coprocessed excipients composed of lactose, HPMC, and PVPP for tableting and its application.

New coprocessed excipients composed of α-lactose monohydrate (a filler), HPMC E3 (a binder), and PVPP (a superdisintegrant) were developed by spray drying in this study to improve the tableting properties of lactose. Factors affecting the properties of the coprocessed excipients were investigated by a 3 × 3 × 2 factorial design. These factors include lactose grade (90 M, 200 M, and 450 M), percentage of HPMC (3.5%, 7.0%, and 10.5%), and percentage of PVPP (0% and 3.5%). The results show that the compactability of the excipients could be significantly improved by increasing either the percentage of HPMC or the primary particle size of lactose. The addition of 3.5% PVPP had little effect on the compactability, but significantly improved the disintegration ability. The developed coprocessed excipients have much lower yield pressures and much higher working efficiency during tableting compared to the main raw material (α-lactose monohydrate). These improvements are mainly attributed to the addition of HPMC and the proximately 30% amorphous lactose formed during process. Both HPMC and amorphous lactose were homogeneously distributed on the surface of the secondary particles, maximizing their effect. Furthermore, the low hygroscopicity and high glass transition temperature of HPMC led to a high yield. The drug loading capacity of the newly coprocessed excipients is also excellent. In summary, the tri-component coprocessed excipients investigated are promising and worthy of further development.

Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis.

New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.