David Carcache

Quinazolinedione sulfonamides: A novel class of competitive AMPA receptor antagonists with oral activity

Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models.

Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects.

The disposition and biotransformation of 14C-radiolabeled mavoglurant were investigated in four healthy male subjects after a single oral dose of 200 mg. Blood, plasma, urine, and feces collected over 7 days were analyzed for total radioactivity, mavoglurant was quantified in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and metabolite profiles were generated in plasma and excreta by high-performance liquid chromatography (HPLC) and radioactivity detection. The chemical structures of mavoglurant metabolites were characterized by LC-MS/MS, wet-chemical and enzymatic methods, NMR spectroscopy, and comparison with reference compounds. Mavoglurant was safe and well tolerated in this study population. Mavoglurant absorption was ≥50% of dose reaching mean plasma Cmax values of 140 ng/ml (mavoglurant) and 855 ng-eq/ml (total radioactivity) at 2.5 and 3.6 hours, respectively. Thereafter, mavoglurant and total radioactivity concentrations declined with mean apparent half-lives of 12 and 18 hours, respectively. The elimination of mavoglurant occurred predominantly by oxidative metabolism involving primarily 1) oxidation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6), and 2) oxidation of the phenyl-ring leading to a hydroxylated metabolite (M3). The subjects were mainly exposed to mavoglurant and seven main metabolites, which combined accounted for 60% of 14C-AUC0–72 h (area under the concentration-time curve from time 0 to infinity). The primary steps of mavoglurant metabolism observed in vivo could partially be reproduced in vitro in incubations with human liver microsomes and recombinant cytochrome P450 enzymes. After 7 days, the mean balance of total radioactivity excretion was almost complete (95.3% of dose) with 36.7% recovered in urine and 58.6% in feces.

6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists.

A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage.

Benzimidazoles as Potent and Orally Active mGlu5 Receptor Antagonists with an Improved PK Profile.

A focused chemical optimization effort of compound 1 based on metabolite elucidation is described, resulting in 15i, a highly potent and selective mGlu5 receptor antagonist with an improved pharmacokinetic profile compared to 1. Characterization of 15i in vivo in the fear-potentiated startle (FPS) paradigm revealed a robust reduction of conditioned fear behavior. This effect nicely correlates with the rat brain pharmacokinetics.

Synthesis and Biological Evaluation of New Triazolo- and Imidazolopyridine RORγt Inverse Agonists

Retinoic‐acid‐related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro‐inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in‐house knowledge, a new series of triazolo‐ and imidazopyridine RORγt inverse agonists was designed. In addition, replacement of the terminal cyclopentylamide metabolic soft spot by five‐membered heterocycles was investigated. From our efforts, we identified an optimal 6,7,8‐substituted imidazo[1,2‐a]pyridine core system and a 5‐tert‐butyl‐1,2,4‐oxadiazole as cyclopentylamide replacement leading to compounds 10 ((S)‐N‐(8‐((4‐(cyclopentanecarbonyl)‐3‐methylpiperazin‐1‐yl)methyl)‐7‐methylimidazo[1,2‐a]pyridin‐6‐yl)‐2‐methylpyrimidine‐5‐carboxamide) and 33 ((S)‐N‐(8‐((4‐(5‐(tert‐butyl)‐1,2,4‐oxadiazol‐3‐yl)‐3‐methylpiperazin‐1‐yl)methyl)‐7‐methylimidazo[1,2‐a]pyridin‐6‐yl)‐2‐methylpyrimidine‐5‐carboxamide). Both derivatives showed good pharmacological potencies in biochemical and cell‐based assays combined with excellent physicochemical properties, including low to medium plasma protein binding across species. Finally, 10 and 33 were shown to be active in a rodent pharmacokinetic/pharmacodynamic (PK/PD) model after oral gavage at 15 mg kg−1, lowering IL‐17 cytokine production in ex vivo antigen recall assays.

Discovery of 1H-pyrrolo[2,3-c]pyridine-7-carboxamides as novel, allosteric mGluR5 antagonists.

1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency.

Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist

A series of potent quinazolinedione sulfonamide antagonists of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA) receptor were designed and synthesized. The structure–activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N‐[7‐isopropyl‐6‐(2‐methylpyrazol‐3‐yl)‐2,4‐dioxo‐1H‐quinazolin‐3‐yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)‐induced generalized tonic–clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy. The X‐ray crystal structure of selurampanel bound to the AMPA receptor hGluA was also obtained.