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编 号：F668254
分子式：C24H19ClF2N2O4S
分子量：504.93
分子式：C24H19ClF2N2O4S
分子量：504.93
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CAS No: 1197420-11-3
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生物活性：
BMS-814580 is an orally active, highly efficacious MCHR1 inhibitor with a Ki of 16.9 nM against hMCHR1. BMS-814580 shows antiobesity activities.
体内研究：
BMS-814580 (0-3 mg/kg; p.o.; once daily for 28 days) shows antiobesity activities in rats.Animal Model:Obese male SD rats, chronic diet-induced obese (DIO) rat model
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
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 Rats8 h rat PK studyb4-day PD studyc day 4 parent compd concn at 20 h
compddosed asaAUC (μM?h)brain (nM)plasma (nM)% weight lossbrain (nM)plasma (nM)
BMS-814580glycinate38.11133045006.4d795512801
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
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 Rataspeciescompd (mg/kg) route of admin Cmax (μM) Tmax (h) AUC0?∞ (μM?h) T1/2 (h) CL (mL/min/kg) Vss(L/kg) F (%)
ratBMS-814580 (1)iv11.5>240.94.1
BMS-814580 phosphate (10)po4.06.710754
aVehicles: iv, PEG400/DMAC/water (70:5:25); po, Methocel/Tween80/water (0.5:0.1:99.4).
体外研究：
BMS-814580 (3.0 μM; 10 min) shows stability with 90%, 95% and 100% remaining in human, rat and mouse liver microsomes, respectively.BMS-814580 displays modest in vitro ion channel inhibition of 43%, 21%, and 15%, respectively, for hERG, Na (4 Hz), and L-type Ca channels at 10 μM.
BMS-814580 is an orally active, highly efficacious MCHR1 inhibitor with a Ki of 16.9 nM against hMCHR1. BMS-814580 shows antiobesity activities.
体内研究：
BMS-814580 (0-3 mg/kg; p.o.; once daily for 28 days) shows antiobesity activities in rats.Animal Model:Obese male SD rats, chronic diet-induced obese (DIO) rat model
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
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 Rats8 h rat PK studyb4-day PD studyc day 4 parent compd concn at 20 h
compddosed asaAUC (μM?h)brain (nM)plasma (nM)% weight lossbrain (nM)plasma (nM)
BMS-814580glycinate38.11133045006.4d795512801
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
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 Rataspeciescompd (mg/kg) route of admin Cmax (μM) Tmax (h) AUC0?∞ (μM?h) T1/2 (h) CL (mL/min/kg) Vss(L/kg) F (%)
ratBMS-814580 (1)iv11.5>240.94.1
BMS-814580 phosphate (10)po4.06.710754
aVehicles: iv, PEG400/DMAC/water (70:5:25); po, Methocel/Tween80/water (0.5:0.1:99.4).
体外研究：
BMS-814580 (3.0 μM; 10 min) shows stability with 90%, 95% and 100% remaining in human, rat and mouse liver microsomes, respectively.BMS-814580 displays modest in vitro ion channel inhibition of 43%, 21%, and 15%, respectively, for hERG, Na (4 Hz), and L-type Ca channels at 10 μM.
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