Distribution- and Metabolism-Based Drug Discovery: A Potassium-Competitive Acid Blocker as a Proof of Concept

Abstract

Conventional methods of drug design require compromise in the form of side effects to achieve sufficient efficacy because targeting drugs to specific organs remains challenging. Thus, new strategies to design organ-specific drugs that induce little toxicity are needed. Based on characteristic tissue niche-mediated drug distribution (TNMDD) and patterns of drug metabolism into specific intermediates, we propose a strategy of distribution- and metabolism-based drug design (DMBDD); through a physicochemical property-driven distribution optimization cooperated with a well-designed metabolism pathway, SH-337, a candidate potassium-competitive acid blocker (P-CAB), was designed. SH-337 showed specific distribution in the stomach in the long term and was rapidly cleared from the systemic compartment. Therefore, SH-337 exerted a comparable pharmacological effect but a 3.3-fold higher no observed adverse effect level (NOAEL) compared with FDA-approved vonoprazan. This study contributes a proof-of-concept demonstration of DMBDD and provides a new perspective for the development of highly efficient, organ-specific drugs with low toxicity.

Design of vonoprazan pyrazole derivatives as potential reversible inhibitors of gastric proton pump: An in silico molecular docking study

“…Namely, this aromatic ring docked to the active site of the gastric proton pump and contributed significantly to the stabilization of the ligand-protein complex by forming the additional interactions with LEU141 (π-σ), ALA335 (π-alkyl), VAL338 (π-alkyl), and CYS813 (π-sulfur) (Figures 7B and 12). In the aforementioned study of Wang and co-workers (20), the pyrrole derivative SH-337 demonstrated very similar binding orientiation compared to our tested compounds. Namely, nitrogen atom of the aliphatic amine formed two donor hydrogen bonds with carbonyl oxygen atoms of residues GLU795 and GLU343.…”

“…On the other hand, Wang and co-workers designed the molecule SH-337, using very similar distribution-based approach as in our study. Molecule SH-337 had a logD7.4 value of 1.3 and a pKa of 9.0 and demonstrated the significantly lower value of docking score (-11.53 kcal/mol) compared to the tested compounds (20).…”

“…In the acidic environment of the stomach, vonoprazan is present predominantly in its ionic form, which has very low cell permeability. Therefore, the drug is rapidly absorbed from the blood into the parietal cell by passive transport, it accumulates there and remains in its ionic form for a long period, even after the nonionic form of vonoprazan has disappeared from the plasma (20).…”