PF-04455242
Abandoned drug for bipolar depression
From Wikipedia, the free encyclopedia
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]
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| Other names | PF-4455242; PF04455242; PF4455242 |
| Routes of administration | Oral[1] |
| Drug class | κ-Opioid receptor antagonist |
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| Formula | C21H28N2O2S |
| Molar mass | 372.53 g·mol−1 |
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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]