RESUMEN
This Letter details our efforts to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M4 receptor.
Asunto(s)
Descubrimiento de Drogas , Pirimidinas/farmacología , Receptor Muscarínico M4/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Receptor Muscarínico M4/metabolismo , Relación Estructura-ActividadRESUMEN
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M4 PAM activity and improved clearance and protein binding profiles.
Asunto(s)
Receptor Muscarínico M4/química , Regulación Alostérica , Amidas/química , Azetidinas/química , Benceno/química , Estructura Molecular , Unión Proteica , Pirazinas/química , Piridinas/química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
Asunto(s)
Descubrimiento de Drogas , Compuestos Heterocíclicos con 2 Anillos/farmacología , Isoquinolinas/farmacología , Proteína Quinasa de Distrofia Miotónica/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 2 Anillos/química , Humanos , Isoquinolinas/química , Estructura Molecular , Proteína Quinasa de Distrofia Miotónica/metabolismo , Relación Estructura-ActividadRESUMEN
This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
Asunto(s)
Aldehído Oxidasa/metabolismo , Miotonía Congénita/metabolismo , Receptor Muscarínico M4/metabolismo , Animales , Descubrimiento de Drogas , Humanos , Ratas , 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
This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.
Asunto(s)
Piperidinas/farmacología , Pirimidinas/farmacología , Quinazolinas/farmacología , Receptor Muscarínico M4/metabolismo , Tiofenos/farmacología , Regulación Alostérica , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Humanos , Microsomas Hepáticos/metabolismo , Piperidinas/síntesis química , Piperidinas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Quinazolinas/síntesis química , Quinazolinas/metabolismo , Ratas , Receptor Muscarínico M4/agonistas , Receptor Muscarínico M4/antagonistas & inhibidores , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/metabolismoRESUMEN
beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.
Asunto(s)
Amidas/síntesis química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácidos Isonicotínicos/síntesis química , Fragmentos de Péptidos/metabolismo , Amidas/química , Amidas/farmacología , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Ácidos Isonicotínicos/farmacocinética , Ácidos Isonicotínicos/farmacología , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit the production of the secreted amino terminal fragment of an artificial amyloid precursor protein in cell culture. In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/síntesis química , Sulfonamidas/síntesis química , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas/química , Sitios de Unión , Línea Celular , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Diseño de Fármacos , Etilaminas/química , Etilaminas/farmacología , Humanos , Modelos Moleculares , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Several simple scoring methods were examined for 2 series of beta-secretase (BACE-1) inhibitors to identify a docking/scoring protocol which could be used to design BACE-1 inhibitors in a drug discovery program. Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cristalografía por Rayos X , Cinética , Modelos Moleculares , Conformación MolecularRESUMEN
A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.