ChemicalBook CAS DataBase List 1197420-11-3

1197420-11-3

Name	Thieno[3,2-d]pyrimidin-4(3H)-one, 6-(4-chlorophenyl)-3-[4-[(3,3-difluoro-1-hydroxycyclobutyl)methoxy]-3-methoxyphenyl]-
CAS	1197420-11-3
Molecular Formula	C24H19ClF2N2O4S
MDL Number	MFCD30829296
Molecular Weight	504.93
MOL File	1197420-11-3.mol

Chemical Properties

Boiling point	691.9±65.0 °C(Predicted)
density	1.49±0.1 g/cm3(Predicted)
pka	12.36±0.40(Predicted)

Hazard Information

Description

BMS-814580 is a Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor with potential anti-obesity property. BMS-814580 exhibits potent binding affinity (Ki = 17 nM) for human MCHR1. BMS-814580 is a potent and selective functional antagonist (Kb = 117 nM) of human MCHR1. In a FLIPR-based assay BMS-814580 exhibiting no activity against MCHR2 at 10 μM. BMS-814580 also exhibits potent binding affinities for cynomolgus monkey and rat MCHR1 (Ki of 4.9 and 11.5 nM, respectively). MCHR1 antagonist demonstrates reduction in feeding and body weight in rats and mice.

Uses

BMS-814580 is an orally active, highly efficacious MCHR1 inhibitor with a Ki of 16.9 nM against hMCHR1. BMS-814580 shows antiobesity activities[1].

in vivo

BMS-814580 (0-3 mg/kg; p.o.; once daily for 28 days) shows antiobesity activities in rats^[1].

Animal Model:	Obese male SD rats, chronic diet-induced obese (DIO) rat model^[1]
Dosage:	0.03, 0.1, 0.3, 1 and 3 mg/kg
Administration:	Orally administered as the phosphate prodrug, once daily for 28 days
Result:	Dose dependently reduced body weight.

Animal Model:

Sprague-Dawley Rats^[1]

Dosage:

10 mg/kg

Administration:

Oral administration, once

Result:

Pharmacokinetics (PK) and Pharmacodynamics (PD) Data: Plasma and Brain Concentrations of Cyclic Tertiary Alcohols and the Effect on Body Weights in Sprague-Dawley Rats

			8 h rat PK study^b		4-day PD study^c	day 4 parent compd	concn at 20 h
compd	dosed as^a	AUC (μM?h)	brain (nM)	plasma (nM)	% weight loss	brain (nM)	plasma (nM)
BMS-814580	glycinate	38.1	11330	4500	6.4^d	7955	12801

^aRats were dosed orally with parent compound or a prodrug; prodrugs doses were adjusted to parent compounds. Vehicle = 0.5% Methocel, 0.1% Tween 80, 99.4% distilled water. ^bDose = 10 mg/kg; plasma and brain concentrations are reported 8 h after dose, n = 2. ^cCompounds were dosed at 3, 10, and 30 mg/kg orally once a day for 4 days; weight loss data is reported only for the 10 mg/kg dose, n = 8; reduction in body weight is reported as % change from baseline body weight compared to vehicle treated animals. NT = not tested. ^dNo biliary lesions were seen in this model.

Animal Model:

Sprague-Dawley Rats^[1]

Dosage:

10 mg/kg (phosphate prodrug) or 1 mg/kg

Administration:

Oral (phosphate prodrug) or intravenous administration (Pharmacokinetic Analysis)

Result:

Pharmacokinetics Data for BMS-814580 in Rat^a

species	compd (mg/kg)	route of admin	C_max (μM)	T_max (h)	AUC_0?∞ (μM?h)	T_1/2 (h)	CL (mL/min/kg)	V_ss(L/kg)	F (%)
rat	BMS-814580 (1)	iv			11.5	>24	0.9	4.1
	BMS-814580 phosphate (10)	po	4.0	6.7	107				54

^aVehicles: iv, PEG400/DMAC/water (70:5:25); po, Methocel/Tween80/water (0.5:0.1:99.4).

References

[1] Ahmad S, et al. Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1 DOI:10.1021/acs.jmedchem.6b00676

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