Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 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
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Data of initial analogs have been shown

    2022-05-16

    Data of initial analogs (±)-– have been shown in wherein SAR was observed for the intended change of the right-hand side pyridin-3-yl ring of to various other -containing heteroaryl ring (Ar) disposing the ring- at different directions. Based on consistent human and rat FAAH potency as well as intrinsic metabolic stability in HLM and RLM, the analogs , and were qualified for the next round of SAR and optimization. Further focus was made on pyridine-3-yl () and pyrimidin-5-yl () analogs wherein the ring substitution SAR, particularly with additional - atom, was studied as in –. Whereas, all other analogs maintained the FAAH potencies, – lost the rat FAAH potency in a commonly observed phenomena in this series that, any electron withdrawing group which could potentially reduce the basicity of the 3-pyridyl-, resulted in particular loss of rat potency. Subsequently, – were also disqualified due to relatively less solubility which were reflected in <10% oral bioavailability in rats (). Based on above SAR inputs, compounds , , – were resolved using chiral prep. HPLC and both the enantiomers (with >96% ee) were screened against FAAH inhibition assay. In all the cases, (−)-enantiomers were found to be >100 fold more potent than (+)-enantiomers irrespective of the human or rat FAAH enzyme (). Based on the comparative FAAH potency of the enantiomers, and supported by the docking analysis, an ()-stereochemistry has been tentatively assigned to the more potent (−)-enantiomers. Profile of the shortlisted (−)-, (−)-, and (−)-– have been presented in which included additional two ADMET evaluation: (a) CYP inhibition; (b) rat PK and ARRY-380 mg penetration. Selectivity against inhibition of major human CYP450 isoforms is an important aspect of modern-day drug optimization as the drug otherwise may lead to potential drug-drug-interactions (DDI). This is particularly important in the area of CIPN where multiple drugs are co-administered. CNS or brain penetration was another important requirement due the adequate therapeutic benefits in NP. As was expected, all the four (−)-enantiomers were near 1 and 10 nM potent in h- and r-FAAH respectively and possessed adequate metabolic stability in HLM and RLM. The observed low intrinsic MR(0.06–0.04 nmol/min/mg) reflected well into the rat PK profile having low plasma clearance (CL), required longer plasma half-life (t) and good oral BA (%F). In addition, all the four compounds were found to be available in brain, indicating CNS penetration of the drugs. Compound (−)-, however, encountered with unacceptable hCYP3A4 inhibition (IC 0.4 µM) in addition to a border line liability for CYP 2C9 and 2C19. The desired optimized lead like properties were achieved in compounds (−)- and (−)- with a balanced profile of FAAH potency (h-IC: 1.3 & 0.6 nM; r-IC: 9.2 & 6.2 nM respectively), selectivity against five major hCYP450 isoforms (>5000 fold), and rat PK properties (46% BA, 50–80% brain penetration). Finally, for the development of FAAH inhibitors, selectivity against a related enzyme, monoacylglycerol lipase (MAGL),, is very important as the latter is primarily responsible for hydrolysis of another endocannabinoid, 2-AG, essential for the brain and CNS functions. We did not see any inhibition of MAGL tested in vitro up to 10 μM of (−)- and (−)- (>10000 fold selectivity). A reversible mechanism of action by this chemotype was established based on a principle of qualitative recovery of FAAH enzyme activity upon dilution of a preincubated enzyme-inhibitor complex. As briefed in , recovery of hFAAH activity, for hydrolysis of its substrate AAMCA, was possible in case of preincubation with the known reversible inhibitors , and (−)-. On the contrary, the enzyme activity could not be recovered when preincubated with the covalent and irreversible inhibitor . Reversible as well a non-substrate like MoA for the FAAH inhibition by (−)- was further confirmed in a separately designed experiment by near 100% recovery of (−)- (quantified by mass spectroscopic method) over a period of 1 h incubation with hFAAH enzyme. In contrast, there was a gradual loss of observed under the similar condition ().