Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket

Abstract

Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the Hloop with a maximum 24 Å movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.

Gold(I)-Catalyzed Tandem Synthesis of Polycyclic Dihydroquinazolinones

“…The method showed good compatibility for electron-withdrawing and electrondonating functional groups such as chloro, bromo, nitro, alkyl, and methoxy groups. The substrates containing electron-withdrawing substituents (1m-p) smoothly afforded the cyclized products 2m-p at room temperature in excellent yields (92-97%, entries [12][13][14][15]. The substrates containing electron-donating substituents (1q-t) also provided the corresponding cyclized products in good to excellent yields (72-91%, entries [16][17][18][19].…”

“…As bioactive alkaloids [4][5][6], dihydroquinazolinones [7][8][9] are not only an important class of compounds but also substructures of structurally complex polycyclic alkaloids with a wide range of biological activities. More specifically, fused dihydroquinazolinones such as cruciferane [10], phaitanthrin D [11], evodiamine [12], and their synthetic congeners [13,14] have attracted medicinal chemists' attention due to their unique structural features and promising bioactivities, which have prompted the research on synthetic dihydroquinazolinones with pharmacological potential (Figure 1). Although various synthetic approaches to bicyclic dihydroquinazolinone scaffolds have been described [15][16][17][18][19][20], effective strategies for more complex tri-and polycyclic dihydroquinazolinones, which operate under mild conditions on readily accessible simple substrates, are rare and of high value.…”

Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety

“…Protocols for the expression and enzyme assay of PDE isoforms were similar to our previous works. − Briefly, the recombined plasmid was transformed into an Escherichia coli competent cell BL21 (CodonPlus), which was grown in a LB medium at 37 °C until A600 to 0.6–0.8, and 0.1 mM isopropyl β- d -thiogalactopyranoside was added for further growth at 15 °C for 24 h. The recombinant proteins were purified by a Ni-NTA column (Qiagen), Q column (GE Healthcare), and Superdex 100 column (GE Healthcare). The enzymatic activities of PDEs were measured by using 3 H-cGMP or 3 H-cAMP (GE Healthcare) as substrates.…”

Therapy for Pulmonary Arterial Hypertension: Glance on Nitric Oxide Pathway

“…Evodiamine is a traditional Chinese medicine for the treatment of cancers ( Dong et al, 2012 ). Evodiamine derivatives (S)-7e and (S)-7 days are newly discovered PDE5 inhibitors with very high selectivity ( Zhang et al, 2020 ). Evodiamine derivative (S)-7 days significantly reduced mPAP and wall thickness in rat MCT-PAH model.…”

“…Currently approved PDE5 inhibitors only bind to the substrate-binding pocket. This novel allosteric pocket regulates both enzymatic activity and pulmonary hemodynamic function of PDE5 thereby serving as a new therapeutic target for PAH treatment ( Zhang et al, 2020 ).…”