Aprepitant 170729-80-3

Molecular Weight: 534.43 Aprepitant is a potent and Selective Neurokinin-1 Receptor Antagonist.


Biological Activity


Aprepitant antagonizes the effects of substance P by binding to NK-1
receptors primarily in the CNS, but also in the periphery. Aprepitant,
at concentrations of 0.1 nM displaces 50% of substance P from hNK1
receptors transfected in CHO or COS cells. In radioligand binding
assays, Aprepitant is 3000-fold selective for the human cloned NK1
receptor versus the human cloned NK3 receptor and >50,000-fold
selective over the human cloned NK2 receptor. In a range of assays at
other human cloned G–protein coupled receptors, Aprepitant retains
>50,000-fold selectivity for the human cloned NK1 receptor.
Aprepitant is inactive in human monoamine oxidase A and B assays and at
human serotonin 5–HT1A, 5–HT2A, 5–HT2c, 5–HT3, 5–HT5, 5–HT6, and 5–HT7
receptors (IC50>3 μM). In the PANLABS panel of radioligand binding
screens using native animal tissues, Aprepitant inhibits [3H]substance
P binding to native NK1 receptors in rat submaxillary gland; there are
no significant interactions of Aprepitant with any Other native animal
G–protein coupled receptors or ion channels examined in the PANLABS
screen. Aprepitant is inactive in monoamine uptake site (NE, 5–HT, DA)
counterscreens using human and animal tissues (IC50> 3 μM)






Aprepitant crosses the blood–brain barrier and occupied NK-1 receptors
in the brain. Aprepitant has been shown to inhibit both acute and
delayed emesis induced by cytotoxic chemotherapeutic such as cisplatin
by blocking substance P. Aprepitant (3 mg/kg i.v. or p.o.) inhibits the
emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection
afforded by Aprepitant (0.1 mg/kg i.v.) is enhanced by combined
treatment with either dexamethasone (20 mg/kg i.v.) or the 5–HT3
receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute
and delayed emesis, ferrets are dosed with cisplatin (5 mg/kg i.p.) and
the retching and vomiting response recorded for 72 h. Pretreatment with
Aprepitant (4–16 mg/kg p.o.) dose-dependently inhibits the emetic
response to cisplatin. Once daily treatment with Aprepitant (2 and 4
mg/kg p.o.) completely prevents retching and vomiting in all ferrets
tested. Further when daily dosing began at 24 h after cisplatin
injection, when the acute phase of emesis had already become
established, Aprepitant (4 mg/kg p.o. at 24 and 48 h after cisplatin)
prevents retching and vomiting in three out of four ferrets. Aprepitant also plays a key part in transmission of pain impulses from
the peripheral receptors to the CNS and is involved in various
behavioural, neurochemical and cardiovascular responses to stress.


Protocol(Only for Reference)


Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	534.43
Formula	C23H21F7N4O3
CAS No.	170729-80-3

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	MK-0869, L-754030

Solubility (25°C) *	In vitro	DMSO	107 mg/mL (200.21 mM)
		Water	<1 mg/mL (
		Ethanol	15 mg/mL (28.06 mM)
	In vivo	30% PEG400/0.5% Tween80/5% propylene glycol	30 mg/mL

Chemical Name	5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one

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