Chemistry:PF-06412562

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PF-06412562, also known as CVL-562, is a moderately potent and highly selective dopamine D1 and D5 receptor partial agonist which is under development for the treatment of the cognitive symptoms of schizophrenia.[1][2][3][4] It is taken orally.[1] The drug has been reported to produce pro-motivational effects in humans.[3][5] PF-06412562 is under development by Pfizer and Cerevel Therapeutics.[1][2] As of August 2025, it is in phase 1/2 clinical trials.[1][2] The drug was also under development for the treatment of Parkinson's disease and cognition disorders, but development for these indications was discontinued.[1][2] Its development for Parkinson's disease was discontinued for business reasons unrelated to safety in 2017.[6]

Chemistry

Synthesis

The chemical synthesis was described (Ex 6):[7]

Protection of 4-Chloro-1H-pyrazolo[4,3-c]pyridine [871836-51-0] (1) with 2,3-Dihydropyran [110-87-2] (2) gives 4-chloro-1-(oxan-2-yl)-1H-pyrazolo[4,3-c]pyridine [1416713-66-0] (3). Suzuki reaction between 4-Methoxy-2-methylphenylboronic acid pinacol ester [214360-68-6] (4) and 5-Bromo-4,6-dimethylpyrimidine [157335-97-2] (5) gives 5-(4-methoxy-2-methylphenyl)-4,6-dimethylpyrimidine [1609259-54-2] (6). Demethylation of the ether gives rise to 4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenol [1609259-55-3] (7). Reaction of this with 3 gives 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1-(oxan-2-yl)pyrazolo[4,5-c]pyridine, PC90116929 (8). Tetramethyl‑di‑tBuXPhos [857356-94-6] is a bulky, electron‑rich biaryl monophosphine ligand used in palladium‑catalysed cross‑coupling reactions. Deprotection of the THP protecting group in acid completed the synthesis of PF2562 (9).

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "PF 6412562". 5 August 2024. https://adisinsight.springer.com/drugs/800038500. 
  2. ↑ 2.0 2.1 2.2 2.3 "Delving into the Latest Updates on PF-06412562 with Synapse". 4 December 2025. https://synapse.patsnap.com/drug/2b65bae6799f4de5840244ffe2e4da7a. 
  3. ↑ 3.0 3.1 "Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia". Schizophrenia Bulletin 48 (1): 199–210. January 2022. doi:10.1093/schbul/sbab095. PMID 34423843. 
  4. ↑ "Advances in the Therapeutic Use of Non-Ergot Dopamine Agonists in the Treatment of Motor and Non-Motor Symptoms of Parkinson's Disease". Current Neuropharmacology 21 (5): 1224–1240. 2023. doi:10.2174/1570159X20666220915091022. PMID 36111769. 
  5. ↑ "Dopaminergic D1 Receptor Stimulation Affects Effort and Risk Preferences". Biological Psychiatry 87 (7): 678–685. April 2020. doi:10.1016/j.biopsych.2019.09.002. PMID 31668477. 
  6. ↑ "Novel Strategies To Activate the Dopamine D1 Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation". Journal of Medicinal Chemistry 62 (1): 128–140. January 2019. doi:10.1021/acs.jmedchem.8b01767. PMID 30525590. 
  7. ↑ Jennifer E. DAVOREN, et al. WO2014072882 (to Pfizer Corp Belgium, Pfizer Corp SRL).



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