Structure-Based Design of Xanthine-Benzimidazole Derivatives as Novel and Potent Tryptophan Hydroxylase Inhibitors

Abstract

Tryptophan hydroxylases catalyze the first and rate-limiting step in the synthesis of serotonin. Serotonin is a key neurotransmitter in the central nervous system and, in the periphery, functions as a local hormone with multiple physiological functions. Studies in genetically altered mouse models have shown that dysregulation of peripheral serotonin levels leads to metabolic, inflammatory, and fibrotic diseases. Overproduction of serotonin by tumor cells causes severe symptoms typical for the carcinoid syndrome, and tryptophan hydroxylase inhibitors are already in clinical use for patients suffering from this disease. Here, we describe a novel class of potent tryptophan hydroxylase inhibitors, characterized by spanning all active binding sites important for catalysis, specifically those of the cosubstrate pterin, the substrate tryptophan as well as directly chelating the catalytic iron ion. The inhibitors were designed to efficiently reduce serotonin in the periphery while not passing the blood−brain barrier, thus preserving serotonin levels in the brain.

Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors

“…Moreover, the introduction of electron-withdrawing ( 9 versus 12 , 16 versus 17 , Table and SI Tables S1 and S2) or electron-donating groups ( 9 versus 10 , Table and SI Tables S1 and S2) at substituent R 3 considerably impacts the potency by increasing or decreasing the inhibitory performance, respectively. This shows the significance of electronic properties at the R 3 substituents for inhibitory potency which is similar to our previous findings for the first generation xanthine benzimidazole inhibitor series . Overall, we observed that the more electron-rich the R 3 substituent is, the stronger the chelating interaction between the N 4 atom of the imidazo­[2,1- b ]­thiazoles and the catalytically active iron atom, and the higher the inhibitory potency.…”

“…They simultaneously occupy, similar to the inhibitor rac- 3 (Figure B), the binding sites of the cosubstrate pterin and the substrate tryptophan, while TPH2 is known to have an approximately 10-fold lower K M value for the cosubstrate pterin compared to TPH1 . Telotristat 1.2 , however, mainly targets the substrate binding site of tryptophan, thus revealing almost identical inhibitory potencies for the two TPH isoforms (Table ).…”

“…(A) Complex with the first generation inhibitor 4 (PDB ID code 7ZII). The benzyl ring of inhibitor 4 is sandwiched between Tyr-235 and Pro-268, directing into the R 2 chain binding pocket and allowing further derivatization in meta and para-position (m, p) of the benzyl ring. (B) Complex with the tricyclic imidazole inhibitor rac- 3 (PDB ID code 8CJO).…”

“…Generally, as described in our initial first generation inhibitor series, the inhibitors have a stronger inhibitory potency toward TPH2 as compared to TPH1. They simultaneously occupy, similar to the inhibitor rac- 3 (Figure B), the binding sites of the cosubstrate pterin and the substrate tryptophan, while TPH2 is known to have an approximately 10-fold lower K M value for the cosubstrate pterin compared to TPH1 .…”

“…In the second sequence the carboxylic acids ( 77 – 78 and 83 – 86 ) were condensed with formerly described 5,6 diamino-pyrimidines using standard peptide coupling reagents TBTU, HOBt, and DIPEA in DMF followed by cyclization to the xanthine core in refluxing NaOH solution. Selective alkylation of the N 7 in the xanthine cores was conducted with 2–3 equiv of alkyl halides in DMF using NaHCO 3 as a weak base (Scheme ).…”