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Pesampator

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
Pesampator
Clinical data
Other namesBIIB-104; PF-04958242
Identifiers
  • N-[(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]oxolan-3-yl]propane-2-sulfonamide
CAS Number
PubChemCID
ChemSpider
UNII
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC18H20N2O4S2
Molar mass392.49 g·mol−1
3D model (JSmol)
  • CC(C)S(=O)(=O)N[C@H]1COC[C@H]1OC2=CC=C(C=C2)C3=CC=C(S3)C#N
  • 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 (INNTooltip International Nonproprietary Name; developmental code namesBIIB-104 andPF-04958242) is apositive allosteric modulator (PAM) of theAMPA receptor (AMPAR), anionotropic glutamate receptor, which was under development byPfizer for the treatment ofcognitive symptoms inschizophrenia.[1][2][3] In March 2018, the development of the drug was transferred over from Pfizer toBiogen.[4] It was also under development for the treatment ofage-relatedsensorineural 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 belongs to thebiarylpropylsulfonamide group of AMPAR PAMs, which also includesLY-404187,LY-503430, andmibampator (LY-451395) among others.[7] It is described as a "high-impact" AMPAR PAM, unlike so-called "low-impact" AMPAR PAMs likeCX-516 and itscongenerfarampator (CX-691, ORG-24448).[2] In animals, low doses of pesampator have been found to enhancecognition andmemory, whereas higher doses producemotor coordinationdisruptions andconvulsions.[2] The same effects, as well asneurotoxicity at higher doses, have been observed withorthosteric and other high-impactallosteric AMPAR activators.[2]

In healthy volunteers, pesampator has been found to significantly reduceketamine-induced deficits inverbal learning andworking memory without attenuating ketamine-inducedpsychotomimetic effects.[2] It was able to complete reverse ketamine-induced impairments inspatial working memory in the participants.[2]

In addition to its actions on the AMPAR, pesampator has been reported to act as aGlyT1glycine transporterblocker.[8][9] As such, it is also aglycine reuptake inhibitor, and may act indirectly to activate theglycine receptor and theglycineco-agonistsite of theNMDA receptor by increasingextracellular levels ofglycine.[8][9]

See also

[edit]

References

[edit]
  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 potentiatorN-{(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. ^abcdefRanganathan 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. ^ab"PF 4958242".AdisInsight. Retrieved2017-08-30.
  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. Retrieved2024-09-05.
  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. ^abSinger 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. ^abMukherjea 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.
Receptor
(ligands)
GlyRTooltip Glycine receptor
NMDARTooltip N-Methyl-D-aspartate receptor
Transporter
(blockers)
GlyT1Tooltip Glycine transporter 1
GlyT2Tooltip Glycine transporter 2
AMPARTooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
KARTooltip Kainate receptor
NMDARTooltip N-Methyl-D-aspartate receptor
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