Fig. 4: Comparison of HBA and HBD-masking on the in vitro PK properties. | Nature Communications

Fig. 4: Comparison of HBA and HBD-masking on the in vitro PK properties.

From: An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides

Fig. 4

1A-6A refer to the amide bonds in 10. The yellow and the blue bars in the individual panels represent the thioamidated (10a–10f) and the N-methylated (10g–10k) counterparts, respectively, at a specific amide bond. a Octanol-water partition coefficient (logD7.4). b Membrane permeability (Pe) of the macrocyclic peptides determined by the PAMPA. c Extent of the peptides to bind non-specifically to plasma proteins determined through Rapid Equilibrium Dialysis (RED) represented in percentage (%). Half-lives (t1/2) of the peptides in d simulated gastric fluid (SGF), and e simulated intestinal fluid (SIF). f Intrinsic clearance (CLint) of the peptides in human liver microsomes deduced from their t1/2 values. Cyclosporin A (CsA) was taken as a control (CLint: 40 ± 5.5 μL min−1 mg−1). n = 3 ± SEM. Each bar represents mean values of three biological replicates: dots are individual data points. Statistical significance was measured against the (all-amide) parent molecule by a one-tailed unpaired t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns (non-significant) > 0.05. p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.0013, 0.0002, 0.0007, 0.0005, 0.0002, 0.0003; p (10 vs 10g, 10h, 10i, 10j, 10k) = 0.0003, <0.0001, 0.0004, 0.0005, 0.0008 for logD7.4. p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.0024, 0.0449, 0.1704, 0.1228, 0.0015, 0.0194; p (10 vs 10g, 10h, 10i, 10j, 10k) = 0.3501, 0.0065, 0.1232, 0.0102, 0.0021 for Pe by PAMPA. p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.1022, 0.0802, 0.0418, 0.0032, 0.0026, 0.0026; p (10 vs 10g, 10h, 10i, 10j, 10k) = 0.0802, 0.0421, 0.1372, 0.0158, 0.3868 for plasma-protein binding. p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.0012, 0.1085, 0.168, 0.107, 0.0008, <0.0001; p (10 vs 10g, 10h, 10i, 10j, 10k) = 0.1142, 0.0095, 0.245, 0.113, 0.0045 for t1/2 in SGF. p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.0002, 0.0023, 0.0509, <0.0001, 0.0007, 0.0080; p (10 vs 10g, 10h, 10i, 10j, 10k) = 0.2716, 0.0081, 0.0001, 0.324, 0.0095 for t1/2 in SIF. p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.0033, 0.0080, 0.0246, 0.0046, 0.0056, 0.0035; p (10 vs 10g, 10h, 10i, 10j, 10k) = 0.0100, 0.0048, 0.0241, 0.0048, 0.0801 for CLint. Source data are provided as a Source Data file.

Back to article page