Table 1. In vitro ADMET profile of... | Rockefeller University Press

Table 1.

In vitro ADMET profile of pyridazine GSMs

Cmpd	Aβ42 IC₅₀^a	clogP^b	Kin. Aq. Sol.^c	FaSSIF/ FeSSIF^d	Metabolic Stability^e			CYP450 IC₅₀ (μM)^f					% PPB^g			hERG^h	P_appⁱ	Efflux Ratio^j	Ames^k
Cmpd	Aβ42 IC₅₀^a	clogP^b	Kin. Aq. Sol.^c	FaSSIF/ FeSSIF^d	H	R	M	3A4	1A2	2C9	2C19	2D6	H	R	M	hERG^h	P_appⁱ	Efflux Ratio^j	Ames^k
1 BPN-15606	7.0	4.40	6.6	>100/ >100	78	84	76	14 (m) 8.9 (t)	37	1.3	6.9	4.7	99.6	99.9	99.8	6.2	37.2	0.9	Positive
2 776890	4.1	3.61	<1.3	80/79	71	76	91	42 (m) 9.4 (t)	12	4.4	12	11	99.8	99.9	99.9	7.3	23.3	0.9	Negative
3 779690	5.3	3.75	<1.3	79/82	100	100	100	19 (m) 17 (t)	3.6	1.3	13	20	99.7	99.7	99.7	3.1	30.2	1.1	Negative

Cmpd	Aβ42 IC₅₀^a	clogP^b	Kin. Aq. Sol.^c	FaSSIF/ FeSSIF^d	Metabolic Stability^e			CYP450 IC₅₀ (μM)^f					% PPB^g			hERG^h	P_appⁱ	Efflux Ratio^j	Ames^k
Cmpd	Aβ42 IC₅₀^a	clogP^b	Kin. Aq. Sol.^c	FaSSIF/ FeSSIF^d	H	R	M	3A4	1A2	2C9	2C19	2D6	H	R	M	hERG^h	P_appⁱ	Efflux Ratio^j	Ames^k
1 BPN-15606	7.0	4.40	6.6	>100/ >100	78	84	76	14 (m) 8.9 (t)	37	1.3	6.9	4.7	99.6	99.9	99.8	6.2	37.2	0.9	Positive
2 776890	4.1	3.61	<1.3	80/79	71	76	91	42 (m) 9.4 (t)	12	4.4	12	11	99.8	99.9	99.9	7.3	23.3	0.9	Negative
3 779690	5.3	3.75	<1.3	79/82	100	100	100	19 (m) 17 (t)	3.6	1.3	13	20	99.7	99.7	99.7	3.1	30.2	1.1	Negative

Cmpd, compound.

^aIC₅₀ represents the concentration in nanomolars of compound required for reducing Aβ42 levels by 50%. The IC₅₀ values are the mean of at least four determinations.

^bCalculated partition coefficient of the ratio of the compound’s concentration in octanol to the compound’s concentration in water using ChemAxon.

^cKinetic solubility measured at pH 7.4 by UV/Vis (visible) absorbance in PBS buffer in micromolar.

^dMeasurement of dissolved compound concentration in FaSSIF or FeSSIF via UV/Vis absorbance.

^ePercent remaining after 30 min on incubation with human (H), rat (R), and mouse (M) liver microsomes (1 mg/ml) at 1-µM test compound concentration.

^fFive recombinant human CYP450 isoforms were tested for inhibition using probe substrates. Percent inhibition was measured by LC-MS/MS analysis. (m), midazolam; (t), testosterone.

^gPercent plasma protein binding (PPB) using human (H), rat (R), and mouse (M) plasma.

^hPatch-Xpress patch-clamp assay; IC₅₀ (in micromolar) based on five-point concentration–response curves (n = 3) in HEK-293 cells stably expressing the hERG channel.

ⁱApparent permeability (A-B; × 10⁻⁶ cm/s) determined in MDR1-MDCK cell monolayers.

^jCalculated efflux ratio determined using MDR1-MDCK cell monolayers (B-A/A-B).

^kNon-GLP screening assay measuring bacterial growth due to the reversion of the histidine mutation induced by incubation with test article (5–100 µM). S. typhimurium bacterial strains, including TA98, TA100, TA1535, and TA1537, in the presence and absence of S9 fraction from Aroclor-induced rat liver.

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