Table 1. Drug-like properties of 1.
| Selectivity (IC50, μM) | Physical properties and stability | Membrane permeability (Papp, 10−6 cm s−1) | Pharmacokinetics |
|---|---|---|---|
| hIDE: 0.06 | Logd7.4: 2.2 | A→B: 1 μM: 3.3 | Cmax (μg ml−1): 4.1 |
| hNEP: 2.6 | Solubility (μM): 58.0 | 10 μM: 2.4 | Cmax (μM): 9.2 |
| hACE: >10.00 | Plasma stability m (t1/2, h): 24.0 | B→A: 1 μM: 19 | tmax (min): 10 |
| hECE: 6.50 | Plasma stability r (t1/2, h): 13.3 | 10 μM: 17 | t1/2 (min): 80 |
| hMMP-1: 10.00 | Plasma stability h (t1/2, h): >24.0 | AUC0→4h (min μg ml−1): 256 | |
| Microsomal stability m (t1/2, min): 20 |
IC50, half-maximal inhibitory concentration; h, human; hIDE, human insulin-degrading enzyme; m, mouse; hMMP-1, matrix metalloprotease 1; NEP, neutral endopeptidase; r, rat.
Selectivity of 1: values are means of two experiments minimum, s.d.±10%; substrate for IDE: native insulin; >10 μM stands for <10% at 10 μM. Physical properties and stability of 1; t1/2>24 h stands for 100% remaining compound at 24 h. Cell membrane permeability of 1 assessed on a Caco-2 cell monolayer; bidirectional transport was measured at 37 °C, for a time period of 1 h (pH: 7.4/7.4); Permeability classification: low=(Papp A→B)<1.0 × 10−6cm s−1; high=(Papp A→B)>1.0 × 10−6 cm s−1. Pharmacokinetic parameters for 1 (30 mg kg−1, ip) injected in male mice (n=3 for each time point) as a DMSO solution.