BMS-378806 357263-13-9

Molecular Weight: 406.43 BMS-378806 Selectively Inhibits the binding of HIV-1 gp120 to the CD4 receptor with EC50 of 0.85-26.5 nM in virus.


Biological Activity


BMS-806, a 7-azaindole derivative, binds gp120 and interferes with the
interaction of HIV surface protein gp120 with the host cell receptor
CD4. BMS-806 inhibits a panel of macrophage- and T cell-tropic HIV-1
strains, which are laboratory strains that use either CCR5 (M-tropic) or
CXR4 (T-tropic) co-receptors to enter cells and are classified as B
subtypes. The aqueous solubility from the crystalline form of BMS-806
(BMS 378806) is 170 μg/mL. The solubility of BMS-806 is 1.3 mg/mL at
pH=2.1 and 3.3 mg/mL at pH=11, a solubility profile that reveals the
amphoteric nature of BMS-806 and estimates the pKa of the
protonated form as 2.9 while that of the free base is approximately 9.6.
BMS-806 competes with soluble CD4 binding to a monomeric form of gp120
in an ELISA assay with IC50 = ~ 100 nM. BMS-806 is specific towards
HIV-1, with no significant inhibitory activity against HIV-2, SIV, MuLV,
RSV, HCMV, BVDV, VSV, and influenza virus observed at concentrations
ranging from 10 to 30 μM and no overt cytotoxicity toward host cells,
CC50 values > 225 μM. BMS-806 binds directly to gp120
at a stoichiometry of approximately 1:1, with a binding affinity similar
to that of soluble CD4. The potential BMS-806 target site is localized
to a specific region within the CD4 binding pocket of gp120 by using
HIV-1 gp120 variants carrying either compound-selected resistant
substitutions or gp120-CD4 contact site mutations.






When BMS-806 is administered dose-proportional increases in the AUC and Cmax is observed. In rat, dog and monkey, plasma levels of drug exceeded the
concentrations required to half-maximally inhibit virus replication in
vitro. The volume of distribution of BMS-806 ranges from 0.4 to 0.6
L/kg, indicative of partitioning beyond plasma; however, examination of
brain levels in the rat revealed minimal CNS penetration. BMS-806 is stable in human, rat, dog and monkey blood at 37 °C during a
2-h incubation. The blood-to-plasma concentration ratios in humans,
rats, dogs and monkeys are 1.1, 0.77, 1.2 and 0.92 (n=3), respectively,
suggesting that BMS-806 is distributed to approximately the same extent
between plasma and blood cells. The human clearance of BMS-806 predicted
from microsomes is 9.2 ml/min/kg (46% of the hepatic blood flow).


Protocol(Only for Reference)


Kinase Assay: [1]

Drug susceptibility Assay

In general, host cells are infected with HIV-1 at a multiplicity of infection (MOI) of 0.005 50% tissue culture infective doses (TCID50)/cell followed by incubation in the presence of serially diluted Inhibitors for 4 to 7 days. Virus yields are quantitated using an RT assay or a p24 enzyme-linked immunosorbent assay (ELISA) (NEN). The results from at least three experiments are used to calculate the 50% effective concentrations (EC50s). The EC50s of IDV, SQV, RTV, and NFV are compared to that of BMS-806 using Dunnett's test. These comparisons are made separately within each assay system. Dunnett's test is used to reduce the probability of false-positive results when a number of treatments are being compared to a control. Confidence bounds for the fold increases in EC50s observes when the same drug is tested in two different assay systems are computed using Fieller's theorem. The use of this theorem is necessary because ratios of parameters (in this case, EC50s) are known not to follow a standard probability distribution, such as the normal distribution. Numbers within the confidence interval are not significantly different from the observed fold increase at the 95% level.

Cell Assay: [1]

Cell lines	MT-2 cells
Concentrations	0-3 mM
Incubation Time	6 days
Method	To determine cytotoxicity, MT-2 cells are incubated in the presence of serially diluted BMS-806 for 6 days and cell viability is quantitated using an XTT [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl-2H-tetrazolium-5-carboxanilide] assay to calculate the 50% cytotoxic concentrations (CC50s).

Animal Study: [1]

Animal Models	Rat, dog and monkey
Formulation	BMS-806 is dissolved in poly (ethylene glycol) 400/ethanol (90:10 v/v).
Dosages	5 mg/kg, 3.4 mg/kg and 3.4 mg/kg.
Administration	BMS-806 is intravenously administered.
Solubility	30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

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

Download BMS-378806 SDF

Molecular Weight (MW)	406.43
Formula	C22H22N4O4
CAS No.	357263-13-9

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	BMS 806

Solubility (25°C) *	In vitro	DMSO	81 mg/mL (199.29 mM)
		Water	<1 mg/mL (
		Ethanol	3 mg/mL (7.38 mM)
	In vivo	30% PEG400/0.5% Tween80/5% propylene glycol	30 mg/mL

Chemical Name	(R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-7H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione

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