Evaluation of Amides, Carbamates, Sulfonamides, and Ureas of 4‑Prop-2-ynylidenecycloalkylamine as Potent, Selective, and Bioavailable Negative Allosteric Modulators of Metabotropic Glutamate Receptor 5

Negative
allosteric modulators (NAMs) of the metabotropic glutamate
receptor 5 (mGlu5) hold great promise for the treatment
of a variety of central nervous system disorders. We have recently
reported that prop-2-ynylidenecycloalkylamine derivatives are potent
and selective NAMs of the mGlu5 receptor. In this work,
we explored the amide, carbamate, sulfonamide, and urea derivatives
of prop-2-ynylidenecycloalkylamine compounds with the aim of improving
solubility and metabolic stability. In silico and experimental analyses
were performed on the synthesized series of compounds to investigate
structure–activity relationships. Compounds 12, 32, and 49 of the carbamate, urea, and
amide classes, respectively, showed the most suitable cytochrome inhibition
and metabolic stability profiles. Among them, compound 12 showed excellent selectivity, solubility, and stability profiles
as well as suitable in vitro and in vivo pharmacokinetic properties.
It was highly absorbed in rats and dogs and was active in anxiety,
neuropathic pain, and lower urinary tract models.