Archives

  • 2018-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • The second approach to optimizing microsomal stability

    2022-06-22

    The second approach to optimizing microsomal stability in this series JTC-801 involved the strategic positioning of steric bulk along the tether as a means of encumbering the access of oxidative enzymes to the methylene bridge. This approach has been employed in other P2-P4 macrocyclic inhibitors of NS3/4A Modeling of with NS3 protease suggested that placement of gem-dimethyl groups at the C2 and C3 positions along the tether would be tolerated since no untoward steric clashes with the enzyme were evident. This approach proved to be successful with , which bears a gem-dimethyl group at the C2 position, and was significantly more stable in HLM than the unsubstituted parent JTC-801 (). Moreover, while the antiviral potency of in the replicons was compromised by approximately 4- to 6-fold, the EC values were still acceptable at less than 5 nM. Replacing the cyclopropyl vinyl group at P1 with a -cyclopropyl gave , a compound with increased metabolic stability accompanied by a 4- to 5-fold loss in potency. The C3 dimethylated compounds and were prepared as matched pairs of and and proved to more potent than those in the C2 methylated series. Based on the results of profiling as well as structural considerations, compounds , , , and were selected for pharmacokinetic (PK) studies in rats. Rat PK profiles were obtained from either a 6 h screen or through a full 24 h study and the data are compiled in . Parent analogue demonstrated low clearance after IV dosing, but exposure after PO administration was poor. The -cyclopropyl derivative also exhibited low clearance after IV dosing, but plasma exposure after PO dosing was significantly improved compared to . The improved oral bioavailability observed after replacing the P1 cyclopropyl vinyl group with a -cyclopropyl moiety in this tripeptide acylsulfonamide series is consistent with previous observations. The PK profile of additional compounds in the P1 -cyclopropyl series were then explored. The introduction of polarity into the methylene tether, as in analogues and , resulted in a PK profile in which oral bioavailability was significantly compromised. However, compound , which bears a gem-dimethyl moiety at C3 of the tether, demonstrated a significant improvement in oral bioavailability when compared to its matched pair, (100% for ; 34% for ). The improvement in the PK profile observed with compared to is consistent with reports suggesting that higher molecular weight (MW) compounds (MW > 500 g/mol) tend to exhibit higher permeability and improved absorption when the Log value is >4.5. Compounds and exhibited the best combination of properties: single digit nM half-maximal inhibitory activity toward GT 1a and 1b HCV replicons, an HLM half-life of greater than 1 h, and improved rat PK profiles compared to , rendering them suitable for evaluation in cardiovascular studies. Compounds and were evaluated in the Langendorff model of cardiac function in which isolated hearts were perfused with test compound for 30 min at a protein–free concentration of 10 µM. The electrocardiograms were monitored and measurements of the heart rate (HR), sinus node recovery time (SNRT), PR, QRS, and QT intervals were recorded and based on absolute changes compared to the drug free control period. Perfusion of at 10 µM resulted in a mild decrease in HR while coronary flow increased transiently (). After approximately 10 min on study, cardiac contractility appeared to weaken, and after 30 min the hearts failed to respond to pacing stimulation and SNRT was not measureable. Prolongation of the QRS interval was also observed. A similar outcome was observed in the cardiovascular assessment of compound . Perfusion of at a concentration of 10 µM for 30 min resulted in a mild decrease in HR, accompanied by a significant prolongation of SNRT, QRS and PR intervals (). These results suggested that both and held a significant cardiovascular liability and no additional studies were conducted on these compounds.