Hélène Catherine Eugénie Rudyk

Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.

Synthesis of 11C-labeled (S,S)-CFMME and (R)-OHDMI and their evaluation as candidate radioligands for imaging norepinephrine transporters with PET

Introduction: (R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDMI) and (S,S)-1-cyclopentyl-2-(5-fluoro2-methoxy-phenyl)-1-morpholin-2-yl-ethanol ((S,S)-CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake (inhibitory constants (K is) were 8.29 and 10.8 nM for (R)-OHDMI and (S,S)-CFMME, respectively, as compared with (S,S)-2-(a-(2methoxyphenoxy)benzyl)morpholine (S,S)-MeNER) which has a Ki of 7.93 nM). Here, we have explored the labeling of these ligands with carbon-11 for evaluation as candidate radioligands for imaging central norepinephrine transporters (NET).