Table 5.

In Vitro ADME Profile for Selected TTR Tetramer Kinetic Stabilizer Compounds

compound	TTR FP IC50 (μM)	solubility (μM)a	microsomal CLint (mL/(min mg))b			liver microsomal stability (% remaining at 30 min)c				predicted half-lifed (H, R, M, monkey)	CYP inhibition (% inhibition at 10 μM) 2C9, 2C19, 2D6, 3A4	%PPBe
			H	R	M monkey	HLM	RLM	MLM	monkey LM			H	R	M
14	0.22	184.5	<0.0231			93	98	102	94	>60 min for all species	02C9—10.4% 2C19—3.1% 2D6—8.1% 3A4—(−)2.2%	83	97	93
20b	0.30	200	<0.0231			108	101	102	102	>60 min for all species	2C9—1.4% 2C19—4.2% 2D6—8.0% 3A4—19.6%	75	78	ND
20d	0.21	200	<0.0231			101	101	97.5	96.7	>60 min for all species	2C9—17.1% 2C19—2.3% 2D6—5.9% 3A4—14.8%	86	91	ND
20c	0.26	200	<0.0231			97.8	96.6	96	100	>60 min for all species	2C9—56.2% 2C19—0.06% 2D6—7.34% 3A4—(−)5.2%	97	97	ND
20e	0.20	200	<0.0231			103	104	98	100	>60 min for all species	2C9—25.2% 2C19—1.85% 2D6—10.0% 3A4—19.5%	91	89	ND
20i	0.60	200	<0.0231			90	105	96	95.2	>60 min for all species	2C9—1.1% 2C19—(−)3.0% 2D6—9.2% 3A4—31.7%	87	93	ND
54	0.26	200	H = 0.0184; R, M, monkey <0.0231			71.4	98.2	91.5	95.7	H = 75.4 min; R, M, monkey <60 min	2C9—26.3% 2C19—(−)4.8% 2D6—0.8% 3A4—18.9%	92	94	ND

^aKinetic solubility measured in PBS (pH = 7.4). When the observed mean solubility is greater than 200 μM, the mean value is adjusted to the maximum assay concentration, which is 200 μM.

^bMicrosomal intrinsic clearance (CL_int); H, human; R, rat; M, mouse; cyno, cynomolgus monkey.

^cLiver microsomal metabolic stability, % of parent drug remaining after a 30 min incubation in the presence of the microsomes; HLM, human liver microsomes; RLM, rat liver microsomes; MLM, mouse liver microsomes; monkey LM, monkey liver microsomes. %Remaining values shown as higher than 100% may be potentially attributed to error.

^dWhen the calculated half-life is longer than the duration of the experiment, the half-life is expressed as greater than the longest incubation time.

^e%PPB, plasma protein binding; H, human; R, rat; M, mouse.