RESUMEN
A scaffold hopping exercise from a monocyclic mGlu2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu2 NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu2 NAM potency, selectivity (versus mGlu3 and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.
Asunto(s)
Amidas/química , Sistema Nervioso Central/metabolismo , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Amidas/metabolismo , Amidas/farmacocinética , Animales , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Pirazoles/química , Piridinas/química , Pirimidinas/química , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50â¯=â¯43â¯nM; AhR activationâ¯=â¯2.3-fold).
Asunto(s)
Inductores del Citocromo P-450 CYP1A2/farmacología , Citocromo P-450 CYP1A2/biosíntesis , Descubrimiento de Drogas , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Regulación Alostérica/efectos de los fármacos , Animales , Antiparkinsonianos/farmacología , Inducción Enzimática/efectos de los fármacos , Humanos , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 µM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).
RESUMEN
The title compound, C3H5N3O8, was synthesized by reacting 2-nitro-propane-1,3-diol with acetyl nitrate. The mol-ecule is bisected by a crystallograpic mirror plane. In the crystal, the mol-ecules pack in a ribbon-like fashion along the c axis, with the central nitro groups pointing in the same direction. C-Hâ¯O contacts apparently provide some additional packing stabilization.
