Discovery and evaluation of Cav3.2-selective T-type calcium channel blockers.

We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.

Discovery and evaluation of Cav3.1-selective T-type calcium channel blockers.

We identified and characterized a series of pyrazole amides as potent, selective Cav3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d, with excellent potencies and/or selectivities toward the Cav3.2- and Cav3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.

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.

Design, Synthesis, and Optimization of Indole Acetic Acid Derivatives as Potent and Selective CRTH2 Receptor Antagonists: Discovery of ACT-774312.

Herein we report the structure-activity relationship (SAR) studies and optimization of new highly potent and selective CRTH2 receptor antagonists as potential follow-ups of our previous reported clinical candidate setipiprant (ACT-129968) for the treatment of respiratory diseases. Structural modification of the amide part of setipiprant (ACT-129968) led to the identification of the tetrahydrocarbazole derivative (S)-B-1 (ACT-453859) ((S)-2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetic acid). This compound which displayed a substantial improvement in potency in the presence of plasma versus setipiprant (ACT-129968) has exhibited an excellent overall pharmacokinetic profile. Further lead optimization to overcome a safety issue as observed in non-clinical studies with (S)-B-1 (ACT-453859), led to the discovery of the 4-azaindole derivative (S)-72 (ACT-774312) ((S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid) which was selected as a potential follow-up of setipiprant (ACT-129968).

A heterogeneous single-atom palladium catalyst surpassing homogeneous systems for Suzuki coupling.

Palladium-catalysed cross-coupling reactions, central tools in fine-chemical synthesis, predominantly employ soluble metal complexes despite recognized challenges with product purification and catalyst reusability1-3. Attempts to tether these homogeneous catalysts on insoluble carriers have been thwarted by suboptimal stability, which leads to a progressively worsening performance due to metal leaching or clustering4. The alternative application of supported Pd nanoparticles has faced limitations because of insufficient activity under the mild conditions required to avoid thermal degradation of the substrates or products. Single-atom heterogeneous catalysts lie at the frontier5-18. Here, we show that the Pd atoms anchored on exfoliated graphitic carbon nitride (Pd-ECN) capture the advantages of both worlds, as they comprise a solid catalyst that matches the high chemoselectivity and broad functional group tolerance of state-of-the-art homogeneous catalysts for Suzuki couplings, and also demonstrate a robust stability in flow. The adaptive coordination environment within the macroheterocycles of ECN facilitates each catalytic step. The findings illustrate the exciting opportunities presented by nanostructuring single atoms in solid hosts for catalytic processes that remain difficult to heterogenize.

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.