piperidines and telcagepant

Calcitonin gene-related peptide (CGRP) signaling inhibitors have shown efficacy in both the acute and preventive treatment of migraine. Telcagepant, a first-generation CGRP receptor antagonist, was effective but failed in clinical trials due to hepatotoxicity. Subsequently, although 4 next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant's failure, more confidence in the liver safety of these compounds was needed. DILIsym v6A, a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI), was used to model all 5 compounds and thus to compare the 4 next-generation CGRP receptor antagonists to telcagepant. In vitro experiments were performed to measure the potential for each compound to inhibit bile acid transporters, produce oxidative stress, and cause mitochondrial dysfunction. Physiologically based pharmacokinetic models were produced for each compound in order to appropriately estimate liver exposure. DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly predicting the observed DILI liability of the first-generation compound. By contrast, DILIsym predicted that each of the 4 next-generation compounds would be significantly less likely to cause DILI than telcagepant. Subsequent clinical trials have validated these predictions for each of the 4 compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant, and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and nonhepatotoxic molecules within the same class.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Chemical and Drug Induced Liver Injury; Computer Simulation; Drug-Related Side Effects and Adverse Reactions; Humans; Imidazoles; Piperidines; Pyridines; Pyrroles; Spiro Compounds

The neuropeptide calcitonin gene-related peptide (CGRP) is found in afferent sensory nerve fibers innervating the resistance arteries and plays a pivotal role in a number of neurovascular diseases such as migraine and subarachnoid bleedings. The present study investigates the binding and antagonistic characteristics of small non-peptide CGRP receptor antagonists (i.e. gepants) in isolated rat brain and mesenteric resistance arteries.. The antagonistic behavior of gepants was investigated in isolated rat mesenteric arteries using a wire myograph setup while binding of gepants to CGRP receptors was investigated in rat brain membranes using a radioligand competitive binding assay. Furthermore, the histological location of the key components of CGRP receptor (RAMP1 and CLR) was assessed by immunohistochemistry.. Our functional studies clearly show that all gepants are reversible competitive antagonists producing Schild plot slopes not significantly different from unity and thus suggesting presence of a uniform CGRP receptor population in the arteries. A uniform receptor population was also confirmed by radioligand competitive binding studies showing similar affinities for the gepants in rat brain and mesenteric arteries, the exception being rimegepant which had 50-fold lower affinity in brain than mesenteric arteries. CLR and RAMP1 were shown to be located in both vascular smooth muscle and endothelial cells of rat mesenteric arteries by immunohistochemistry.. The present results indicate that, despite species differences in the CGRP receptor affinity, the antagonistic nature of these gepants, the distribution pattern of CGRP receptor components and the mechanism behind CGRP-induced vasodilation seem to be similar in resistance-sized arteries of human and rats.

Topics: Aged; Aged, 80 and over; Animals; Azepines; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Calcitonin Receptor-Like Protein; Cerebellum; Cerebral Arteries; Dipeptides; Dose-Response Relationship, Drug; Endothelial Cells; Female; Humans; Imidazoles; In Vitro Techniques; Ligands; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Myography; Piperazines; Piperidines; Protein Binding; Pyridines; Quinazolines; Radioligand Assay; Rats, Sprague-Dawley; Receptor Activity-Modifying Protein 1; Receptors, Calcitonin Gene-Related Peptide; Spiro Compounds; Sus scrofa; Vasodilation; Vasodilator Agents