Prodrugs of pioglitazone for extended-release (XR) injectable formulations.

N-Acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model candidates for extended-release injectable formulations. All PIO derivatives prepared are crystalline solids as determined by powder X-ray diffraction, and the solubility in aqueous media is below 1 µM at 37 °C. The melting points steadily increase from 55 °C, for the hexanoyloxymethyl derivative, to 85 °C, for the palmitoyloxymethyl derivative; inversely, the solubilities in ethyl oleate decrease as a function of increasing acyl chain length. The butyroyloxymethyl ester has a higher melting point and a lower solubility in ethyl oleate than expected from the trend. The (13)C solid-state NMR spectra of the PIO homologues between the hexanoyloxymethyl derivative and stearoyloxymethyl derivative suggest a common structural motif with the acyl chains exchanging between two distinct conformations, and the rate of exchange is slower for longer chain derivatives. The butyroyloxymethyl derivative is efficiently converted to PIO in in vitro rat plasma with a half-life of <2 min at 37 (o) C, while the rate of enzymatic cleavage in rat plasma decreases as the ester chain length increases for the longer acyloxymethyl derivatives. The concentration of PIO in plasma increases rapidly, or "spikes," in the hours following intramuscular (IM) injection of either the HCl salt or the butyroyloxymethyl derivative. In contrast, the more lipophilic palmitoyloxymethyl derivative provides slow growth in the PIO concentration over the first day to reach levels that remain steady for 2 weeks. On the basis of its in vivo pharmacokinetic profile, as well as material and solubility properties, the PIO palmitoyloxymethyl derivative has potential as a once-monthly injectable medication to treat diabetes.

Structure-activity relationships and hepatic safety risks of thiazole agonists of the thrombopoietin receptor.

5-F substitution of an aminothiazole moiety within a series of thrombopoietin receptor agonists leads to potent agents with an improved hepatic safety profile in rodent toxicology studies.

The identification of orally bioavailable thrombopoietin agonists.

Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.

Pyrimidine benzamide-based thrombopoietin receptor agonists.

A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.

Piperazinyl CCR1 antagonists--optimization of human liver microsome stability.

The synthesis, biological activity, and pharmacokinetic profile of CCR1 antagonists are described.