Pesampator

Pesampator (INNTooltip International Nonproprietary Name; developmental code names BIIB-104 and PF-04958242) is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Pfizer for the treatment of cognitive symptoms in schizophrenia.^[1][2][3] In March 2018, the development of the drug was transferred over from Pfizer to Biogen.^[4] It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness.^[3][5] In July 2022, Biogen discontinued the development of pesampator for cognitive symptoms in schizophrenia due to ineffectiveness.^[6]

Pesampator

Clinical data
Other names	BIIB-104; PF-04958242
Identifiers
IUPAC name N-[(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]oxolan-3-yl]propane-2-sulfonamide
CAS Number	1258963-59-5
PubChem CID	49853967
ChemSpider	32698813
UNII	9G1A824CC2
CompTox Dashboard (EPA)	DTXSID001337272
Chemical and physical data
Formula	C18H20N2O4S2
Molar mass	392.49 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C)S(=O)(=O)N[C@H]1COC[C@H]1OC2=CC=C(C=C2)C3=CC=C(S3)C#N
InChI InChI=1S/C18H20N2O4S2/c1-12(2)26(21,22)20-16-10-23-11-17(16)24-14-5-3-13(4-6-14)18-8-7-15(9-19)25-18/h3-8,12,16-17,20H,10-11H2,1-2H3/t16-,17+/m0/s1 Key:TTYKUKSFWHEBLI-DLBZAZTESA-N

Pesampator belongs to the biarylpropylsulfonamide group of AMPAR PAMs, which also includes LY-404187, LY-503430, and mibampator (LY-451395) among others.^[7] It is described as a "high-impact" AMPAR PAM, unlike so-called "low-impact" AMPAR PAMs like CX-516 and its congener farampator (CX-691, ORG-24448).^[2] In animals, low doses of pesampator have been found to enhance cognition and memory, whereas higher doses produce motor coordination disruptions and convulsions.^[2] The same effects, as well as neurotoxicity at higher doses, have been observed with orthosteric and other high-impact allosteric AMPAR activators.^[2]

In healthy volunteers, pesampator has been found to significantly reduce ketamine-induced deficits in verbal learning and working memory without attenuating ketamine-induced psychotomimetic effects.^[2] It was able to complete reverse ketamine-induced impairments in spatial working memory in the participants.^[2]

In addition to its actions on the AMPAR, pesampator has been reported to act as a GlyT1 glycine transporter blocker.^[8][9] As such, it is also a glycine reuptake inhibitor, and may act indirectly to activate the glycine receptor and the glycine co-agonist site of the NMDA receptor by increasing extracellular levels of glycine.^[8][9]

See also

• AMPA receptor positive allosteric modulator
• List of investigational antipsychotics

References

1. Shaffer CL, Patel NC, Schwarz J, Scialis RJ, Wei Y, Hou XJ, Xie L, Karki K, Bryce DK, Osgood SM, Hoffmann WE, Lazzaro JT, Chang C, McGinnis DF, Lotarski SM, Liu J, Obach RS, Weber ML, Chen L, Zasadny KR, Seymour PA, Schmidt CJ, Hajós M, Hurst RS, Pandit J, O'Donnell CJ (2015). "The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242)". J. Med. Chem. 58 (10): 4291–308. doi:10.1021/acs.jmedchem.5b00300. PMID 25905800.
2. Ranganathan M, DeMartinis N, Huguenel B, Gaudreault F, Bednar MM, Shaffer CL, Gupta S, Cahill J, Sherif MA, Mancuso J, Zumpano L, D'Souza DC (2017). "Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242". Mol. Psychiatry. 22 (11): 1633–1640. doi:10.1038/mp.2017.6. PMID 28242871. S2CID 3691566.
3. "PF 4958242". AdisInsight. Retrieved 2017-08-30.
4. "BIOGEN TO ACQUIRE FROM PFIZER FIRST-IN-CLASS PHASE 2b READY ASSET FOR COGNITIVE IMPAIRMENT ASSOCIATED WITH SCHIZOPHRENIA" (PDF). 12 March 2018.
5. Bednar MM, DeMartinis N, Banerjee A, Bowditch S, Gaudreault F, Zumpano L, Lin FR (2015). "The Safety and Efficacy of PF-04958242 in Age-Related Sensorineural Hearing Loss: A Randomized Clinical Trial". JAMA Otolaryngol Head Neck Surg. 141 (7): 607–13. doi:10.1001/jamaoto.2015.0791. PMID 25997115.
6. "biib-20221231". www.sec.gov. Retrieved 2024-09-05.
7. Froestl W, Muhs A, Pfeifer A (2012). "Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors". J. Alzheimers Dis. 32 (4): 793–887. doi:10.3233/JAD-2012-121186. PMID 22886028.
8. Singer P, Dubroqua S, Yee BK (2015). "Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?". Curr. Pharm. Des. 21 (26): 3771–87. doi:10.2174/1381612821666150724100952. PMID 26205290.
9. Mukherjea D, Ghosh S, Bhatta P, Sheth S, Tupal S, Borse V, Brozoski T, Sheehan KE, Rybak LP, Ramkumar V (2015). "Early investigational drugs for hearing loss". Expert Opin Investig Drugs. 24 (2): 201–17. doi:10.1517/13543784.2015.960076. PMC 5488860. PMID 25243609.