Molecular Modeling, Design, Synthesis, and Biological Activity of 1<i>H</i>-Pyrrolo[2,3-<i>c</i>]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers

Abstract

A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.Key words potassium-competitive acid blocker (P-CAB); peptic ulcer; acid-related disease; 1H-pyrrolo [2,3-c]pyridine-7-amine; gastric acid secretion; gastroesophageal reflux disease (GERD) Current therapies for gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases either prevent the stimulation of parietal cells (e.g., H 2 receptor antagonists, H 2 RAs) or inhibit gastric H + /K + -ATPase (e.g., proton pump inhibitors, PPIs).1) Despite their potent inhibitory activities against acid secretion and their worldwide clinical application, it is suggested that the current treatment could be improved in several aspects.2) Potassium-competitive acid blockers (P-CABs), a new class of acid suppressants with a different mode of action from the existing therapies, are expected to offer some therapeutic benefits such as better symptom control and faster healing of GERD as well as other acid-related diseases.Over the past 30 years, various companies have focused on developing P-CABs as alternative acid suppressants.3)From our efforts to develop new P-CABs, we found a 1H-pyrrolo[2,3-c] pyridine-7-amine derivative 1 (Fig. 1, Left) has potent H + /K + -ATPase inhibitory activity (IC 50 27 nM). Recently, Panchal et al. also reported this compound and its derivatives as P-CABs.4) The acid secretion inhibitory activity in rats of this compound was 62% at the dose of 1 mg/kg on intravenous (i.v.) administration. This result encouraged us to explore more potent compounds in this derivative. In order to design potent inhibitors, we created the homology model of the luminal region of H + /K + -ATPase from the crystal structure of Ca 2+ -ATPase (PDB ID, 1IWO) 5) using SCWRL ver. 2.9. 6) We identified two lipophilic cavities (LP-1 and LP-2 sites) and two polar residues (Tyr925 and Tyr928) in the enzyme that could be used to improve inhibitory activity. 7,8) Figure 1 displays the docking model of compound 1 and also the target LP-1, LP-2 sites and two Tyr residues. This model suggested that this compound binds to the enzyme mainly via the LP-1 site (mode A).In order to improve the in vitro inhibitory activity, we used the following two strategies. First, the 7-position of PCABs has been considered as a possible target for improving inhibitory activity because the orthogonal conformation of benzyl substituents has a major impact on inhibitory activity in a series of imidazo[1,2-a] pyridine compounds.9) Next, we anticipated that the inhibitory activity could be improved via additional lipophilic and po...

Recent Advances in the Synthesis and Biological Activity of Pyrrolo[2,3-c]pyridines

“…The Bartoli reaction is also used and described for synthesizing 2-alkyl-substituted or 2,3-dialkylsubstituted pyrrolo[2,3-c]pyridines 7, among the functionalized derivatives of which potent potassium-competitive acid blockers (P-CABs) have been identified (Scheme 3) [14].…”

Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs)

“…(2), 3 PF-03716556 (3), 4 and soraprazan (BAY-359) (4) 5 ], pyrrolopyridazines (CS-526 (5) 6 ), and pyrrolopyiridines (6), 7,8,9 have been investigated as P-CABs (Fig. 1).…”