PF-04455242 explained

Width:250px
Routes Of Administration:Oral
Class:κ-Opioid receptor antagonist
Atc Prefix:None
Cas Number:1202647-54-8
Pubchem:44599828
Chemspiderid:26610764
Unii:Y3530Z78QD
Chembl:1818341
Synonyms:PF-4455242; PF04455242; PF4455242
Iupac Name:2-methyl-N-4-(2-pyrrolidin-1-ylsulfonylphenyl)phenylmethyl]propan-1-amine
C:21
H:28
N:2
O:2
S:1
Smiles:CC(C)CNCC1=CC=C(C=C1)C2=CC=CC=C2S(=O)(=O)N3CCCC3
Stdinchi:1S/C21H28N2O2S/c1-17(2)15-22-16-18-9-11-19(12-10-18)20-7-3-4-8-21(20)26(24,25)23-13-5-6-14-23/h3-4,7-12,17,22H,5-6,13-16H2,1-2H3
Stdinchikey:OWVIKBRKPCTDEP-UHFFFAOYSA-N

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. It is taken by mouth.

Pharmacology

The drug is a selective KOR antagonist and shows approximately 10- to 20-fold higher affinity for the KOR (Ki = 1–3nM) over the μ-opioid receptor (MOR) (Ki = 10–64nM) and has negligible affinity for the δ-opioid receptor (DOR) (Ki > 4,000nM). 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. However, PF-04455242 also showed a variety of other weak off-target activities.

Clinical studies

PF-04455242 reached phase 1 clinical trials for bipolar depression prior to the discontinuation of its development in 2010. Its development was discontinued upon unfavorable toxicological findings in animals that had been exposed to the drug for 3months. 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. It was in phase 1 trials by 2009 and was first described in the scientific literature by 2010.[6] [7] [8]

See also

External links

Notes and References

  1. Web site: PF 4455242 . AdisInsight . Springer Nature Switzerland AG . 29 September 2010 . 28 September 2024.
  2. Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, Shao L, Qiu Z . Major Depressive Disorder and Kappa Opioid Receptor Antagonists . Translational Perioperative and Pain Medicine . 1 . 2 . 4–16 . 2016 . 27213169 . 4871611 .
  3. Urbano M, Guerrero M, Rosen H, Roberts E . Antagonists of the kappa opioid receptor . Bioorganic & Medicinal Chemistry Letters . 24 . 9 . 2021–2032 . May 2014 . 24690494 . 10.1016/j.bmcl.2014.03.040 .
  4. Melief EJ, Miyatake M, Carroll FI, Béguin C, Carlezon WA, Cohen BM, Grimwood S, Mitch CH, Rorick-Kehn L, Chavkin C . 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 . 21832171 . 3198912 . 10.1124/mol.111.074195 .
  5. Margolis EB, Wallace TL, Van Orden LJ, Martin WJ . Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology . PLOS ONE . 15 . 12 . e0232864 . 2020 . 33373369 . 7771853 . 10.1371/journal.pone.0232864 . 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. . free .
  6. Jacobsen L, Banerjee A, Byon W, Huang Y, Carson RE, Tomasi G, Weinzimmer D, Williams W, Lin S, Ropchan J, McCarthy T . 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 . 2010 . 40 .
  7. Verhoest PR, Basak AS, Parikh V, Hayward M, Kauffman GW, Paradis V, McHardy SF, McLean S, Grimwood S, Schmidt AW, Vanase-Frawley M, Freeman J, Van Deusen J, Cox L, Wong D, Liras S . 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 . 21744827 . 10.1021/jm2006035 .
  8. Grimwood S, Lu Y, Schmidt AW, Vanase-Frawley MA, Sawant-Basak A, Miller E, McLean S, Freeman J, Wong S, McLaughlin JP, Verhoest PR . 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 . 21821697 . 10.1124/jpet.111.185108 .

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