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.

Figure 1

Tissue niche-mediated drug distribution (TNMDD) of vonoprazan. (1) After administration and absorption, vonoprazan migrates into the cytoplasm of parietal cells from plasma via passive transport. (2) Vonoprazan then migrates into the acidic secretory canaliculus from the cytoplasm via passive transport and becomes protonated. (3) Protonated vonoprazan, which shows low membrane permeability, cannot migrate back into the cytoplasm and thus accumulates, remaining in a protonated state over a long period even after the nonionic form in the plasma and the cytoplasm is eliminated.

Figure 2

Metabolite analysis and binding model of vonoprazan and M-IV. (a) Metabolites of vonoprazan in human hepatocytes. (b) Crystal structure of gastric H⁺, K⁺-ATPase in complex with vonoprazan [41]. (c) Binding model showing M-IV bound to H⁺, K⁺-ATPase. ^aValues obtained from an in vitro metabolic profile of vonoprazan with human hepatocytes [42].

Figure 3

Overall strategy for distribution- and metabolism-based drug design of new P-CABs. Due to the acidic niches of the stomach, vonoprazan is specifically targeted to the stomach, resulting in a 3.2-fold greater distribution in the stomach than in the liver; however, vonoprazan metabolism produces toxic metabolites, and long-term systemic exposure to high levels of these toxic metabolites can result in systemic side effects. Based on our newly developed design strategy, we introduced an additional substituent to simultaneously promote absorption and improve the distribution ratio to ensure effectiveness. This substituent also introduces a metabolic soft spot for direct and rapid metabolization of the drug that accumulates in the systemic compartment, but not that in the stomach, into nontoxic metabolites to improve the safety profile of the new P-CAB.

Figure 4

Molecular design of new P-CABs. (a) Molecular design of new P-CAB SH-337 based on DMBDD strategy. (b) Binding model showing the designed P-CAB SH-337 with H⁺, K⁺-ATPase.

Figure 5

Proposed SH-337 metabolic pathway in the hepatocytes or liver microsomes of rat and human. ^aPercentages of all SH-337 metabolites in rat and human microsomes after a 30 and 60 min incubation period. ^bPercentages of all SH-337 metabolites in rat and human hepatocytes after a 60 and 120 min incubation period.