Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases.

Migration of immune cells to sites of inflammation is a critical step in the body's response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit.

A uniquely efficacious type of CFTR corrector with complementary mode of action.

Three distinct pharmacological corrector types (I, II, III) with different binding sites and additive behavior only partially rescue the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding and trafficking defect observed in cystic fibrosis. We describe uniquely effective, macrocyclic CFTR correctors that were additive to the known corrector types, exerting a complementary "type IV" corrector mechanism. Macrocycles achieved wild-type-like folding efficiency of F508del-CFTR at the endoplasmic reticulum and normalized CFTR currents in reconstituted patient-derived bronchial epithelium.

Discovery of Clinical Candidate ACT-777991, a Potent CXCR3 Antagonist for Antigen-Driven and Inflammatory Pathologies.

The CXCR3 chemokine receptor is a G protein-coupled receptor mainly expressed on immune cells from the lymphoid lineage, including activated T cells. Binding of its inducible chemokine ligands CXCL9, CXCL10, and CXCL11 leads to downstream signaling events and the migration of activated T cells to sites of inflammation. Herein, we report the third part of our CXCR3 antagonist program in the field of autoimmunity, culminating in the discovery of the clinical compound ACT-777991 ().

Contractions of Human-iPSC-derived Cardiomyocyte Syncytia Measured with a Ca-sensitive Fluorescent Dye in Temperature-controlled 384-well Plates.

Spontaneously contracting syncytia of cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CM) are a useful model of human cardiac physiology and pharmacology. Various methods have been proposed to record this spontaneous activity and to evaluate drug effects, but many of these methods suffer from limited throughput and/or physiological relevance. We developed a high-throughput screening system to quantify the effects of exogenous compounds on hiPSC-CM's beating frequency, using a Ca-sensitive fluorescent dye and a temperature-controlled imaging multi-well plate reader.

Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

Discovery and evaluation of Ca3.2-selective T-type calcium channel blockers.

We identified and characterized a series of pyrrole amides as potent, selective Ca3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Ca3.

Milestones to the Discovery of T-type Calcium Channel Blockers for the Treatment of Generalized Epilepsies.

We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series.

Discovery and evaluation of Ca3.1-selective T-type calcium channel blockers.

We identified and characterized a series of pyrazole amides as potent, selective Ca3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d, with excellent potencies and/or selectivities toward the Ca3.

Synthesis and Characterization of Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Antibacterial Activity against Gram-Negative Bacteria.

There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens.

Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.

Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site.

Preparation, Antiepileptic Activity, and Cardiovascular Safety of Dihydropyrazoles as Brain-Penetrant T-Type Calcium Channel Blockers.

A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.

Novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram positive activity and improved safety profile.

Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies.

Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of drug-induced torsades de pointes in humans.

Background: The issue of drug-induced QT interval prolongation and torsades de pointes represents a major concern for pharmaceutical development. In this investigation, we examined the value of the isolated rabbit Purkinje fibre as an in vitro action potential (AP) assay to predict the potential of drugs to induce these undesirable adverse effects.

Methods: First, we categorised the proarrhythmic risk of 26 medicinal products based on proportional reporting ratios for these two adverse events recorded in a US FDA database (Spontaneous Reporting System/Adverse Event Reporting System).