Khaled J. Barakat

Determination of brain and plasma drug concentrations by liquid chromatography/tandem mass spectrometry

A method is described for the evaluation of drug concentrations in plasma and brain from treated rats. The analyte is recovered from plasma or brain homogenate by liquid-liquid extraction and subsequently analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). A simple experimental protocol renders the procedure valuable for obtaining information rapidly on brain penetration and plasma exposure of specific classes of compounds. This methodology has been applied to evaluate brain penetration with 30 different compounds from the same discovery program. In an attempt to increase throughput in our screening efforts, mixture dosing was evaluated. Results from single compound administration were compared with results following administration of a mixture of four compounds. Preliminary results, with specific classes of compounds, show no major differences (ranking order) in brain or plasma concentrations between mixture dosing and single compound administration, suggesting that mixture dosing could be applicable to brain penetration studies in the drug discovery phase.

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues.

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.

Peptidomimetic growth hormone secretagogues: synthesis and biological activities of analogs varied at the indole nucleus of the prototypical spiropiperidine L-162,752

Abstract SAR studies around the indole nucleus of the prototypical peptidomimetic L-162,752 revealed that the D-Trp could be replaced with 3-phenylpropyl-D-glycine and O-benzyl-D-serine to provide secretagogues with comparable intrinsic activity but with significantly better oral activity in dogs. Use of dimethyl β-alanine amino side-chains led to a considerable loss of activity in the D-homophenylalanine and O-benzyl-D-serine series.