Long-term distribution of biodegradable microparticles in rat muscle quantified noninvasively by MRI.

PURPOSE: To demonstrate the feasibility of MRI to monitor longitudinally the fate of PLGA microparticles in muscle tissue after intramuscular injection in rats using standard equipment. METHODS: MRI was performed at different time points and until day 28 after intramuscular administration of microparticles. Image segmentation was used to quantify the MRI signals. Histology was performed at selected time points to validate the in vivo observations. The SOM230-long acting release formulation was used as test compound. RESULTS: Microparticles were detected in vivo until 28 days following their administration. Imaging and histology data indicated that the MRI signals followed three phases: in an early phase (≤ 48 h after injection), vehicle, edema and hydration of microparticles contributed to the signals. In the second (days 3-17) and third phases (day 17 onward), microparticle hydration was the main contributor. SOM230 in blood displayed peaks at days 2 and 17. CONCLUSION: MRI was suitable to follow longitudinally the presence of PLGA microparticles in the rat muscle without labeling them. This is advantageous, because labeling could potentially alter the properties and pharmacokinetics of the microparticles. Data were consistent with an initial compound release followed by diffusion and microparticle erosion as main mechanisms of SOM230 release.

Tetrazole-based deoxyamodiaquines: synthesis, ADME/PK profiling and pharmacological evaluation as potential antimalarial agents.

A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77nM against chloroquine-resistant K1- and W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories.

Synthesis and in vitro and in vivo pharmacological evaluation of new 4-aminoquinoline-based compounds.

A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitro. Pharmacokinetic studies on 3d and 3e in mice showed that they had moderate half-life (4-6 h) and low oral bioavailability. The front runner compound 3d exhibited moderate inhibition of the malaria parasite on P. berghei infected mice following oral administration (5 mg/kg), achieving reduction of parasitemia population by 47% on day 7.

Penta-substituted benzimidazoles as potent antagonists of the calcium-sensing receptor (CaSR-antagonists).

A series of novel benzimidazole derivatives has been designed via a scaffold morphing approach based on known calcilytics chemotypes. Subsequent lead optimisation led to the discovery of penta-substituted benzimidazoles that exhibit attractive in vitro and in vivo calcium-sensing receptor (CaSR) inhibitory profiles. In addition, synthesis and structure-activity relationship data are provided.