MK-4409

Formula

C₂₂H₁₇ClFN₃O₂S

Molar mass

441.90 g·mol⁻¹

CAS

1207745-58-1

PubChem CID

53341130

Origin

A wholly synthetic compound with no natural occurrence. It was produced within pharmaceutical development and was not commercialised.

InChIKey

DBZMCSVIITXLCC-UHFFFAOYSA-N

Editorial estimate, not clinical.

MK-4409 belongs to the generation of fatty acid amide hydrolase inhibitors designed to address pain by an indirect route. The reasoning is as follows: rather than activating the CB1 receptor everywhere in the brain, which inevitably produces the intoxicating and cognitive effects of cannabinoids, one prevents the destruction of the endocannabinoids the body manufactures. Since these are produced on demand, at the sites where signalling is solicited, the elevation remains in principle localised where it is useful. Chobanian and colleagues describe in 2014 the complete optimisation path that led to this molecule, starting from a high-throughput screening hit and pursued simultaneously on three fronts, in vitro inhibitory potency, pharmacokinetic profile and efficacy in rodent models of inflammatory and neuropathic pain. The compound belongs to the oxazole-core inhibitors, chemically distinct from the carbamates and ureas that inactivate the enzyme covalently. That therapeutic class did not keep its promises. No amide hydrolase inhibitor has been approved, and the phase 1 trial of the Portuguese compound BIA 10-2474, conducted in Rennes in 2016, caused one death and serious neurological lesions in several volunteers; later analyses attributed the toxicity to a non-selective inhibition of several brain lipases rather than to blockade of the target enzyme itself. That episode continues to condition the regulatory assessment of the whole class.

An entirely chemical route, described here by class only. The molecule is built around an oxazole core bearing a fluorophenyl and a thioether group linked to a chloropyridine, the whole being completed by a pyridine substituted with a tertiary alcohol. It belongs to the family of non-covalent inhibitors of the amide hydrolase, distinct from the carbamates and ureas that inactivate the enzyme irreversibly.

Sources: EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA. Our method.

Class

ECS modulator (research)

Origin

A wholly synthetic compound with no natural occurrence. It was produced within pharmaceutical development and was not commercialised.

Status

Unscheduled

1. 1.Chobanian et coll. 2014 : découverte du MK-4409, inhibiteur oxazole de la FAAH pour la douleur inflammatoire et neuropathiquePMID 24944750