Simulation of the Impact of Atropisomer Interconversion on Plasma Exposure of Atropisomers of an Endothelin Receptor Antagonist

Abstract

BMS-207940, a potent endothelin receptor antagonist, exists as rapidly interconverting atropisomers. The plasma interconversion t(1/2) is approximately 2.5 hours at 400 microg/mL under room temperature and decreases to < 0.1 hours at 20 microg/mL, making it extremely difficult to conduct pharmacokinetic studies of individual atropisomers. The pharmacokinetics of the 50/50 racemate of BMS-207940 in humans were reasonably described by a one-compartmental model with an apparent terminal elimination t(1/2) of 15 hours. Given the above rates, simulations were conducted based on a one-compartmental model to explore the possible range of individual rates of atropisomer elimination and potential difference in plasma exposure to the two atropisomers. Simulations demonstrated that the elimination rates of the individual atropisomers are bounded between 0 and 0.046 h(-1) and between 0.046 and 0.092 h(-1), respectively. The estimation of the upper bounds for atropisomer elimination rate constants is robust and relatively insensitive to the rate of atropisomer interconversion compared to the rate of racemate elimination. Simulations of the administration of a single atropisomer or the 50/50 racemate, based on all the possible scenarios of individual atropisomer elimination, showed little difference in plasma exposure to the two atropisomers. Potential differences in plasma exposure to the two atropisomers depend, to a larger extent, on the ratio of the rate of atropisomer interconversion versus racemate elimination and, to a lesser extent, on the conformation of atropisomers administered. When atropisomer interconversion is 10-fold or more rapid than racemate elimination, the largest possible difference in plasma exposure between the two atropisomers is below 20%, regardless of the route and conformation of the atropisomer(s) administered.

Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2R)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

“…The 1 H NMR spectrum of 6 at room temperature (298 K) in DMSO-d 6 showed clearly two sets of peaks due to two atropisomers 6A and 6B. The 6-methyl group of uracil exhibited two sharp singlets at 2.044 and 2.062 ppm for the two isomers, respectively.…”

“…1-(2,6-Difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (6), a potent and orally active gonadotropin-releasing hormone (GnRH) receptor antagonist, was initially found to exist as a mixture of two isomers in DMSO-d 6 , CD 3 OD, D 2 O, C 6 D 6 , and CDCl 3 . The proton, carbon, and fluorine NMR spectra in these solvents clearly showed two sets of signals at room temperature.…”

“…Similarly, the acetate salt of 6 (2 mg) was dissolved in 5 ml of DMSO-d 6 and added to 500 ml of 20 mM sodium phosphate buffered D 2 O (pH = 6.5) with 50 mM NaCl and immediately put into the magnet for NMR experiments (6 was not soluble at pH = 7.5). Proton NMR spectra were recorded at 10-min intervals, starting at 20 min after initial dissolution of the sample.…”

“…BMS-207940 (4) is a potent endothelin receptor antagonist, existing as a pair of atropisomers that interconvert in aqueous media following first-order kinetics, with a half-life of 15.8 h at a concentration of 0.4 mg/ml. 6 Several amides such as ZM374979 (5a) are potent and selective NK 1 antagonists in clinical development. 7 5a possesses four atropisomers, which are stable enough to be separated at room temperature.…”

Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF‐06463922) and Desmethyl Congeners

“…and DS°= 0.0243 kcal mol À1 K. These parameters provide ac alculated Gibbs energy of activation DG°to be 24.6 kcal mol À1 at physiological temperature (37 8 8C), which corresponds to a t 1/2 of approximately 6hours in this medium. [31] With this data in hand, it was also important to establish the stability of the macrocyclic compound, lorlatinib (2)a nd determine the chiral integrity.Ananalogous experiment was set up on the iChem Explorer heating as ample of lorlatinib (spiked with the enantiomer 3 to ensure both compounds are detected in the chiral assay). After 24 hours at 65 8 8Ci nI PA , no chiral erosion of the sample material was detected (see Supporting Information).…”