PF-4840154

PF-4840154
Names
	Preferred IUPAC name N-Benzyl-4-[(2-methylpropyl)amino]-2-{4-[(oxan-3-yl)methyl]piperazin-1-yl}pyrimidine-5-carboxamide
Identifiers
CAS Number	1332708-14-1;
3D model (JSmol)	Interactive image;
ChEMBL	ChEMBL1818218 ;
ChemSpider	26610754 ;
IUPHAR/BPS	6309;
PubChem CID	53380803;
CompTox Dashboard (EPA)	DTXSID001029756 ;
	InChI InChI=1S/C26H38N6O2/c1-20(2)15-27-24-23(25(33)28-16-21-7-4-3-5-8-21)17-29-26(30-24)32-12-10-31(11-13-32)18-22-9-6-14-34-19-22/h3-5,7-8,17,20,22H,6,9-16,18-19H2,1-2H3,(H,28,33)(H,27,29,30) Key: PPANZCQXFYBGHN-UHFFFAOYSA-N ;
	SMILES O=C(NCC1=CC=CC=C1)C(C=N2)=C(NCC(C)C)N=C2N(CC3)CCN3CC4CCCOC4;
Properties
Chemical formula	C26H38N6O2
Molar mass	466.630 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

PF-4840154 is a pyrimidine derivative discovered by Pfizer at its Sandwich, Kent research center. The compound is a potent, selective activator of both the human (EC₅₀ = 23 nM) and rat (EC₅₀ = 97 nM) TRPA1 channels.^[1] This compound elicits nociception in a mouse model through TRPA1 activation. PF-4840154 is used as a reference agonist of the TRPA1 channel for in-vitro high-throughput screening purposes, and is superior to allyl isothiocyanate for this use.^[2] The TRPA1 channel is considered an attractive pain target based on the fact that TRPA1 knockout mice showed near complete attenuation of pain behaviors in some pre-clinical development models.^[3]^[4]

References

^ Samanta, Amrita; Kiselar, Janna; Pumroy, Ruth A.; Han, Seungil; Moiseenkova-Bell, Vera Y. (2018-04-27). "Structural insights into the molecular mechanism of mouse TRPA1 activation and inhibition". Journal of General Physiology. 150 (5). Rockefeller University Press: 751–762. doi:10.1085/jgp.201711876. ISSN 0022-1295. PMC 5940248. PMID 29703838.
^ Ryckmans T, Aubdool AA, Bodkin JV, Cox P, Brain SD, Dupont T, Fairman E, Hashizume Y, Ishii N, Kato T, Kitching L, Newman J, Omoto K, Rawson D, Strover J (July 2011). "Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel". Bioorg. Med. Chem. Lett. 21 (16): 4857–4859. doi:10.1016/j.bmcl.2011.06.035. PMID 21741838.
^ McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (August 2007). "TRPA1 mediates formalin-induced pain". Proc. Natl. Acad. Sci. U.S.A. 104 (33): 13525–30. doi:10.1073/pnas.0705924104. PMC 1941642. PMID 17686976.
^ McMahon SB, Wood JN (March 2006). "Increasingly irritable and close to tears: TRPA1 in inflammatory pain". Cell. 124 (6): 1123–5. doi:10.1016/j.cell.2006.03.006. PMID 16564004.

[1] Samanta, Amrita; Kiselar, Janna; Pumroy, Ruth A.; Han, Seungil; Moiseenkova-Bell, Vera Y. (2018-04-27). "Structural insights into the molecular mechanism of mouse TRPA1 activation and inhibition". Journal of General Physiology. 150 (5). Rockefeller University Press: 751–762. doi:10.1085/jgp.201711876. ISSN 0022-1295. PMC 5940248. PMID 29703838.

[pmid21741838-2] Ryckmans T, Aubdool AA, Bodkin JV, Cox P, Brain SD, Dupont T, Fairman E, Hashizume Y, Ishii N, Kato T, Kitching L, Newman J, Omoto K, Rawson D, Strover J (July 2011). "Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel". Bioorg. Med. Chem. Lett. 21 (16): 4857–4859. doi:10.1016/j.bmcl.2011.06.035. PMID 21741838.

[pmid17686976-3] McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (August 2007). "TRPA1 mediates formalin-induced pain". Proc. Natl. Acad. Sci. U.S.A. 104 (33): 13525–30. doi:10.1073/pnas.0705924104. PMC 1941642. PMID 17686976.

[pmid16564004-4] McMahon SB, Wood JN (March 2006). "Increasingly irritable and close to tears: TRPA1 in inflammatory pain". Cell. 124 (6): 1123–5. doi:10.1016/j.cell.2006.03.006. PMID 16564004.

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See also

References