PF-04455242 - Misplaced Pages

(Redirected from PF-4455242) Abandoned drug for bipolar depression

Pharmaceutical compound

PF-04455242
Clinical data

Other names	PF-4455242; PF04455242; PF4455242
Routes of administration	Oral
Drug class	κ-Opioid receptor antagonist
ATC code	None
Identifiers
IUPAC name 2-methyl-N-methyl]propan-1-amine
CAS Number	1202647-54-8
PubChem CID	44599828
ChemSpider	26610764
UNII	Y3530Z78QD
ChEMBL	ChEMBL1818341
CompTox Dashboard (EPA)	DTXSID30152783
Chemical and physical data
Formula	C₂₁H₂₈N₂O₂S
Molar mass	372.53 g·mol
3D model (JSmol)	Interactive image
SMILES CC(C)CNCC1=CC=C(C=C1)C2=CC=CC=C2S(=O)(=O)N3CCCC3
InChI InChI=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 Key: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. 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 (K_i = 1–3 nM) over the μ-opioid receptor (MOR) (K_i = 10–64 nM) and has negligible affinity for the δ-opioid receptor (DOR) (K_i > 4,000 nM). It is a "short-acting" or non-inactivating antagonist of the KOR (as opposed to irreversible antagonists like JDTic). 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 (I_max ≈ 50%). 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 3 months. 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.

References

^ "PF 4455242". AdisInsight. Springer Nature Switzerland AG. 29 September 2010. Retrieved 28 September 2024.
^ Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, et al. (2016). "Major Depressive Disorder and Kappa Opioid Receptor Antagonists". Translational Perioperative and Pain Medicine. 1 (2): 4–16. PMC 4871611. PMID 27213169.
^ Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorganic & Medicinal Chemistry Letters. 24 (9): 2021–2032. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
Melief EJ, Miyatake M, Carroll FI, Béguin C, Carlezon WA, Cohen BM, et al. (November 2011). "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. doi:10.1124/mol.111.074195. PMC 3198912. PMID 21832171.
Margolis EB, Wallace TL, Van Orden LJ, Martin WJ (2020). "Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology". PLOS ONE. 15 (12): e0232864. doi:10.1371/journal.pone.0232864. PMC 7771853. PMID 33373369. Although PF-04455242 is reported to be a full antagonist in heterologous systems , 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 . 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.
Jacobsen L, Banerjee A, Byon W, Huang Y, Carson RE, Tomasi G, et al. (2010). "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.
Verhoest PR, Basak AS, Parikh V, Hayward M, Kauffman GW, Paradis V, et al. (August 2011). "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. doi:10.1021/jm2006035. PMID 21744827.
Grimwood S, Lu Y, Schmidt AW, Vanase-Frawley MA, Sawant-Basak A, Miller E, et al. (November 2011). "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. doi:10.1124/jpet.111.185108. PMID 21821697.