Chemistry:PF-04455242

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PF-04455242 is an experimental κ-opioid receptor (KOR) antagonist which was under development by Pfizer for the treatment of bipolar depression but was never marketed.[1][2][3] Its development was discontinued in early clinical trials.[2][3] It is taken by mouth.[1]

Pharmacology

The drug is a selective KOR antagonist and shows approximately 10- to 20-fold higher affinity for the KOR (Ki = 1–3 nM) over the μ-opioid receptor (MOR) (Ki = 10–64 nM) and has negligible affinity for the δ-opioid receptor (DOR) (Ki > 4,000 nM).[2][3] It is a "short-acting" or non-inactivating antagonist of the KOR (as opposed to irreversible antagonists like JDTic).[4] Although originally characterized as a KOR neutral antagonist however, subsequent research revealed in 2020 that PF-04455242 is actually only a moderately efficacious partial antagonist of the KOR (Imax ≈ 50%).[5] In any case, the drug reversed the analgesic and prolactin-elevating effects of the KOR agonist spiradoline in animals, showed efficacy in animal models predictive of antidepressant activity, and reversed stress-induced reinstatement of cocaine-seeking behavior.[2][3] However, PF-04455242 also showed a variety of other weak off-target activities.[2][3]

Clinical studies

PF-04455242 reached phase 1 clinical trials for bipolar depression prior to the discontinuation of its development in 2010.[1][3] Its development was discontinued upon unfavorable toxicological findings in animals that had been exposed to the drug for 3 months.[2][3] Along with JDTic, which was also discontinued due to toxicity findings early in clinical trials, PF-04455242 was one of the first KOR antagonists to be developed for potential treatment of psychiatric disorders.[2] It was in phase 1 trials by 2009[1] and was first described in the scientific literature by 2010.[6][7][8]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "PF 4455242". AdisInsight. Springer Nature Switzerland AG. 29 September 2010. https://adisinsight.springer.com/drugs/800030611. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Major Depressive Disorder and Kappa Opioid Receptor Antagonists". Translational Perioperative and Pain Medicine 1 (2): 4–16. 2016. PMID 27213169. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Antagonists of the kappa opioid receptor". Bioorganic & Medicinal Chemistry Letters 24 (9): 2021–2032. May 2014. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494. 
  4. ↑ "Duration of action of a broad range of selective κ-opioid receptor antagonists is positively correlated with c-Jun N-terminal kinase-1 activation". Molecular Pharmacology 80 (5): 920–929. November 2011. doi:10.1124/mol.111.074195. PMID 21832171. 
  5. ↑ "Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology". PLOS ONE 15 (12). 2020. doi:10.1371/journal.pone.0232864. PMID 33373369. Bibcode: 2020PLoSO..1532864M. "Although PF-04455242 is reported to be a full antagonist in heterologous systems [36], we found that it only partially blocked the U-69,593 responses in the electrophysiology assay (Fig 1B). We observed a maximal blockade asymptoting towards 45% of the baseline U-69,593 responses by 100 nM PF-04455242. The concentration of PF-04455242 that produced half of the maximum effect for this antagonist is 6.7 ± 15.1 nM. These data indicate that PF-04455242 is a partial antagonist in this tissue. [...] PF-04455242 showed some unexpected results in the characterization studies performed here compared to previously described pharmacological properties [27, 36]. First, we found it to only have partial antagonist action, with maximal blockade of the U-69,593 response plateauing at approximately 50%. [...] Together, these observations indicate PF-04455242 is quite different from a neutral KOR selective antagonist.". 
  6. ↑ "Central receptor occupancy and pharmacodynamic action of PF-04455242, a high affinity, selective kappa opioid receptor antagonist, in humans.". Society for Neuroscience Abstract Viewer and Itinerary Planner 40. 2010. https://scholar.google.com/scholar?cluster=16284020634444796693. 
  7. ↑ "Design and discovery of a selective small molecule κ opioid antagonist (2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242)". Journal of Medicinal Chemistry 54 (16): 5868–5877. August 2011. doi:10.1021/jm2006035. PMID 21744827. 
  8. ↑ "Pharmacological characterization of 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a high-affinity antagonist selective for κ-opioid receptors". The Journal of Pharmacology and Experimental Therapeutics 339 (2): 555–566. November 2011. doi:10.1124/jpet.111.185108. PMID 21821697. 



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