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Pyrimidine derivative chemical
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
ChEMBL
ChemSpider
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)
N Key: PPANZCQXFYBGHN-UHFFFAOYSA-N
N
O=C(NCC1=CC=CC=C1)C(C=N2)=C(NCC(C)C)N=C2N(CC3)CCN3CC4CCCOC4
Properties
C 26 H 38 N 6 O 2
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).
Chemical compound
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]
See also
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 .
TRPA
Activators
4-Hydroxynonenal
4-Oxo-2-nonenal
4,5-EET
12S-HpETE
15-Deoxy-Δ12,14 -prostaglandin J2
α-Sanshool (ginger , Sichuan and melegueta peppers )
Acrolein
Allicin (garlic )
Allyl isothiocyanate (mustard , radish , horseradish , wasabi )
AM404
ASP-7663
Bradykinin
Cannabichromene (cannabis )
Cannabidiol (cannabis )
Cannabigerol (cannabis )
Cinnamaldehyde (cinnamon )
CR gas (dibenzoxazepine; DBO)
CS gas (2-chlorobenzal malononitrile)
Cuminaldehyde (cumin )
Curcumin (turmeric )
Dehydroligustilide (celery )
Diallyl disulfide
Dicentrine (Lindera spp.)
Farnesyl thiosalicylic acid
Formalin
Gingerols (ginger )
Hepoxilin A3
Hepoxilin B3
Hydrogen peroxide
Icilin
Isothiocyanate
JT-010
Ligustilide (celery , Angelica acutiloba )
Linalool (Sichuan pepper , thyme )
Methylglyoxal
Methyl salicylate (wintergreen )
N-Methylmaleimide
Nicotine (tobacco )
Oleocanthal (olive oil )
Paclitaxel (Pacific yew )
Paracetamol (acetaminophen)
PF-4840154
Phenacyl chloride
Polygodial (Dorrigo pepper )
Shogaols (ginger , Sichuan and melegueta peppers )
Tear gases
Tetrahydrocannabinol (cannabis )
Tetrahydrocannabiorcol
Thiopropanal S-oxide (onion )
Umbellulone (Umbellularia californica )
WIN 55,212-2
Blockers
TRPC
TRPM
TRPML
TRPP
TRPV
Activators
2-APB
5',6'-EET
9-HODE
9-oxoODE
12S-HETE
12S-HpETE
13-HODE
13-oxoODE
20-HETE
α-Sanshool (ginger , Sichuan and melegueta peppers )
Allicin (garlic )
AM404
Anandamide
Bisandrographolide (Andrographis paniculata )
Camphor (camphor laurel , rosemary , camphorweed , African blue basil , camphor basil )
Cannabidiol (cannabis )
Cannabidivarin (cannabis )
Capsaicin (chili pepper )
Carvacrol (oregano , thyme , pepperwort , wild bergamot , others)
DHEA
Diacyl glycerol
Dihydrocapsaicin (chili pepper )
Estradiol
Eugenol (basil , clove )
Evodiamine (Euodia ruticarpa )
Gingerols (ginger )
GSK1016790A
Heat
Hepoxilin A3
Hepoxilin B3
Homocapsaicin (chili pepper )
Homodihydrocapsaicin (chili pepper )
Incensole (incense )
Lysophosphatidic acid
Low pH (acidic conditions)
Menthol (mint )
N-Arachidonoyl dopamine
N-Oleoyldopamine
N-Oleoylethanolamide
Nonivamide (PAVA) (PAVA spray )
Nordihydrocapsaicin (chili pepper )
Paclitaxel (Pacific yew )
Paracetamol (acetaminophen)
Phenylacetylrinvanil
Phorbol esters (e.g., 4α-PDD )
Piperine (black pepper , long pepper )
Polygodial (Dorrigo pepper )
Probenecid
Protons
RhTx
Rutamarin (Ruta graveolens )
Resiniferatoxin (RTX) (Euphorbia resinifera /pooissonii )
Shogaols (ginger , Sichuan and melegueta peppers )
Tetrahydrocannabivarin (cannabis )
Thymol (thyme , oregano )
Tinyatoxin (Euphorbia resinifera /pooissonii )
Tramadol
Vanillin (vanilla )
Zucapsaicin
Blockers