Table 2. Detailed Profile for Compound 4 (BMS-932481).

assay					result
Aβ1–42 IC50 (nM); n = 12					6.6 ± 2.3
Aβ1–40 IC50 (nM); n = 3					25 ± 8
Aβx-42 IC50 (nM); n ≥ 3					5.5 ± 3.6
total Aβ1–x inhib. at 50 μM (%); n ≥ 3					30 ± 10
AMES result					negative
metabolic stability T1/2: human, rat, mouse, cynomolgus monkey, dog (min)					30, 28, 36, 11, 27
plasma free fraction: human, rat, mouse, cynomolgus monkey, dog (%)					0.6, 0.7, 0.7, 1.3, 0.8
CYP 450 HLM inhibition IC50 (μM) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4					>40, > 40, 4.5, 7.4, 8.3, 18, 0.2
CYP 3A4 HLM time-dependent inhib.
		KI (μM)			83
		Kinact (min –1)			0.47
hERG IC50 (μM)					1.2
Caco-2 Papp, efflux ratio					3.5, 0.8
PSA (Å2)					90
pKa, spectrophotometric					2.0, 5.9
shake flask log D at pH 6.5, 7.4a					3.97, 4.34
melting point (°C)					230
aq. solubilityb at pH 1.0, 6.5 (μg/mL)					19, 0.1
iv PK parameters			speciesc
			ratd	monkeye		doge
	t1/2 (h)		2.7 ± 0.6	2.9 ± 1.0		8.7 ± 1.1
	CL (mL/min/kg)		11.2 ± 0.4	31.3 ± 9.5		12.5 ± 1.2
	Vss (L/kg)		2.3 ± 0.4	5.4 ± 0.8		6.1 ± 0.3
	F (%)f		98	45		85
projected human PK parametersg
	dose (mg QD)				110, 446
	Cmax (μM)				0.32, 1.30
	AUC (μM·h)				4.0, 16.2
	Aβ1–42 reduction (%)				31, 57

^aOctanol/water partitioning.

^bCrystalline material.

^cSprague–Dawley rat, male cynomolgus monkey, male Beagle dog, pretreated with pentagastrin.

^d2 mg/kg, 5 min iv infusion, 9:1 PEG:EtOH, n = 5.

^e1 mg/kg, 5 min iv infusion, 9:1 PEG:EtOH, n = 3.

^fDosed as a nanosuspension.

^gAt steady state.