Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite

Abstract

Screening of a metalloprotease library led to the identification of a thiol-based dual ACE/NEP inhibitor as a potent ACE2 inhibitor. Modifications of the P(1) benzyl moiety led to improvements in ACE2 potency as well as to increased selectivity versus ACE and NEP.

Graphical abstract

Scheme 1

Reagents and conditions: (a) 2c and 2e, XS, AcCl, NEt₃, dioxane, 0 °C to rt, 15–37%; (b) 2k, 2m, and 2n, XO, AcSH, DIAD, PPh₃, THF, 0 °C to rt, 24–67%; (c) 2a–2b, 2d, 2f–2j, 2l, 2o–2s, XNH, HBr, NaNO₂, H₂O, 0 °C, 25–80%; (d) AcS⁻K⁺, DMF, 0 °C to rt, 11–72%; (e) EDC, HOAt, i-Pr₂NEt, CH₂Cl₂, 48–96%; (f) LiOH·H₂O, THF, H₂O, 30–94%.

Figure 1

A model of the thiol compound 1i bound to the active site of ACE2 based on a X-ray co-crystal structure of a carboxylate inhibitor bound to ACE2 (PDB code 1R4L). The ACE2 carbons are colored cyan with inhibitor 1i carbons colored green. The semi-transparent gray surface represents the molecular surface, while hydrogen bonds are depicted as yellow dashed lines. Several residues were removed for visual clarity. This figure was generated using PYMOL version 1.0 (Delano Scientific, www.pymol.org).

Figure 2

A close up of the P¹ pocket of the model of the thiol compound 1i bound to the active site of ACE2 based on a X-ray co-crystal structure (PDB code 1R4L). The ACE2 carbons are colored cyan with inhibitor 1i carbons colored green. ⁵¹⁰Tyr is colored in orange to highlight its putative role in the selectivity of 1i. The semi-transparent gray surface represents the molecular surface. This figure was generated using PYMOL version 1.00 (Delano Scientific, www.pymol.org).

Figure 3

A model of the thiol compound 1i bound to the active site of ACE using the X-ray co-crystal structure of ACE and lisinopril (PDB code 1O86). The ACE carbons are colored magenta with inhibitor 1i carbons colored green. ⁵¹⁸Val is colored orange to highlight its hypothesized role in the selectivity of 1i. The semi-transparent gray surface represents the molecular surface. This figure was generated using PYMOL version 1.00 (Delano Scientific, www.pymol.org).