PF-04455242

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]

PF-04455242

Clinical data
Other names	PF-4455242; PF04455242; PF4455242
Routes of administration	Oral[1]
Drug class	κ-Opioid receptor antagonist
ATC code	None
Identifiers
IUPAC name 2-methyl-N-[[4-(2-pyrrolidin-1-ylsulfonylphenyl)phenyl]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−1
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

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).^[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 (I_max ≈ 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

• κ-Opioid receptor § Antagonists
• List of investigational antidepressants