Romain Siegrist

Identification of a New Chemical Class of Antimalarials

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.

Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold

A novel series of anti-malarials, based on a hydroxy-ethyl-amine scaffold, initially identified as peptidomimetic protease inhibitors is described. Combination of the hydroxy-ethyl-amine anti-malarial phramacophore with the known Mannich base pharmacophore of amodiaquine (57) resulted in promising in vivo active novel derivatives.

Structure–Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT-462206: a Potent, Brain-Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist

The orexin system consists of two G‐protein‐coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB‐649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT‐462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non‐rapid eye movement (non‐REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT‐462206 shows anxiolytic‐like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.

Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure–activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1

Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.

Substituted pyrrolidin-2-ones: Centrally acting orexin receptor antagonists promoting sleep. Part 2.

Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the γ-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3-hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats.

UV-triggered Affinity-Capture Identifies Interactions Between the Plasmodium falciparum Multidrug Resistance Protein 1 (PfMDR1) and Antimalarial Agents in Live Parasitized Cells

Background: We have previously identified potent novel antimalarial compounds with an unknown mode of action. Results: A photo-reactive affinity capture method was used to identify parasite proteins that interact with these antimalarials. Conclusion: ACT-213615 interacts with Plasmodium falciparum multidrug resistance protein 1 (PfMDR1). Significance: This photo-reactive affinity capture method can be generally used to identify drug targets in live cells. A representative of a new class of potent antimalarials with an unknown mode of action was recently described. To identify the molecular target of this class of antimalarials, we employed a photo-reactive affinity capture method to find parasite proteins specifically interacting with the capture compound in living parasitized cells. The capture reagent retained the antimalarial properties of the parent molecule (ACT-213615) and accumulated within parasites. We identified several proteins interacting with the capture compound and established a functional interaction between ACT-213615 and PfMDR1. We surmise that PfMDR1 may play a role in the antimalarial activity of the piperazine-containing compound ACT-213615.

Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action

More than 40 % of the worlds population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub‐Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine‐based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT‐451840 [(S,E)‐N‐(4‐(4‐acetylpiperazin‐1‐yl)benzyl)‐3‐(4‐(tert‐butyl)phenyl)‐N‐(1‐(4‐(4‐cyanobenzyl)piperazin‐1‐yl)‐1‐oxo‐3‐phenylpropan‐2‐yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.

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.

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. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.