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

• Published in: Biopharmaceutics & drug disposition Vol. 41; no. 4-5; pp. 166 - 183
• Main Authors: Murgasova, Renata, Carreras, Ester Tor, Suetterlin‐Hachmann, Martina, Silva Torrao, Leonel Reis, Kittelmann, Matthias, Alexandra, Vargas, Fredenhagen, Andreas
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2020
• Subjects: Analgesics; Analgesics - blood; Analgesics - chemistry; Analgesics - pharmacokinetics; Analgesics - urine; Angiotensin; Angiotensin II; Angiotensin II Type 2 Receptor Blockers - blood; Angiotensin II Type 2 Receptor Blockers - chemistry; Angiotensin II Type 2 Receptor Blockers - pharmacokinetics; Angiotensin II Type 2 Receptor Blockers - urine; Animals; Benzhydryl Compounds - blood; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacokinetics; Benzhydryl Compounds - urine; Bile; Biotransformation; Blood Proteins - metabolism; Carboxylic acids; Cells, Cultured; Chronic pain; Dogs; Dosage; Drug dosages; Enantiomers; Feces - chemistry; Female; Gastrointestinal tract; Hepatocytes; Hepatocytes - metabolism; Humans; Hydroxylation; Intestinal microflora; Intestine; Investigations; Isoquinolines - blood; Isoquinolines - chemistry; Isoquinolines - pharmacokinetics; Isoquinolines - urine; Kidneys; Macaca fascicularis; Male; metabolic pathway; Metabolic pathways; Metabolites; Mice, Inbred ICR; Microsomes, Liver - metabolism; pain; pharmacokinetics; Rats, Long-Evans; Rats, Sprague-Dawley; Species; Stereoisomerism; Tetrahydroisoquinoline; angiotensin; pharmacokinetics; metabolic pathway; pain
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.2226

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 (AT2R) 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 14C‐ 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.