Non-clinical characterization of the disposition of EMA401, a novel small molecule angiotensin II type 2 receptor (AT2R) antagonist.

EMA401, (the S-enantiomer of 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), also known as Olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT2 R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain. The main purpose of the present work was to investigate the disposition of a single 14 C- labeled EMA401 in non-clinical studies. The in vitro metabolism studies of EMA401 were undertaken to understand the hepatic biotransformation pathways in animal species used in toxicology studies and how they compare to human. Furthermore, investigation of EMA401's PK was carried out in vivo in rats. The study demonstrates the rapid absorption and distribution of drug-related material mainly to the tissues associated with absorption and elimination (GI tract, liver, and kidney). EMA401was then readily eliminated metabolically via the bile (95% of dose) predominantly in the form of the direct acylglucuronide (40% of dose), which was further hydrolysed by the intestinal flora to the active parent drug. Other metabolic pathways such as dealkylations and hydroxylation were also involved in the elimination of EMA401 to a lesser extent. EMA401 was metabolically unstable in hepatocytes of all species investigated and the key metabolites produced in the in vitro model were also detected in vivo. Independent of the dosing route, the S-enantiomer EMA401 showed a good in vivo chiral stability. Overall, the present study provides the first full characterization of the disposition of EMA401 in preclinical species.

Magnetic solid-phase extraction of angiotensin II receptor antagonists in human urine and plasma with a reversed-phase/cation-exchange mixed-mode sorbent.

Biocompatible magnetic nanoparticles that featured divinylbenzene and sulfonate functionalities were used for the magnetic solid-phase extraction of five angiotensin II receptor antagonists from human urine and plasma samples based on a reversed-phase and cation-exchange mixed-mode mechanism. Under the optimized extraction conditions, coupled to high-performance liquid chromatography with fluorescence detection, this proposed method was found to be accurate and precise with relative standard deviations of less than 11.7%, and a good recovery of 80.1-119.5% for both samples. The linear ranges were 0.2-2000 and 0.2-2500 ng/mL along with correlation coefficients above 0.9923 and 0.9928 for urine and plasma samples, respectively. Limits of detection were 0.01-5.74 and 0.01-1.31 ng/mL, respectively. The proposed magnetic solid-phase extraction based on the magnetic nanoparticles functionalized with divinylbenzene and sulfonate was a reliable and convenient sample pretreatment method and had the potential for isolating and enriching the angiotensin II receptor antagonists in biological samples.