From Wikipedia, the free encyclopedia
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