RESUMEN
Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal of corticotropin releasing hormone receptor-1 antagonist was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and cocrystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability. To ensure the stability throughout the shelf life, "prototype" formulations of salts and cocrystal in tablet form were stored at 40 °C and several water vapor pressures. Disproportionation kinetics were studied in these prototype tablet formulations using two-dimensional X-ray diffractometry. Formulations containing the adipic acid cocrystal or heminapadisylate salt did not show disproportionation of API when stored at 40 °C/75% RH for 300 days. On the other hand, formulations containing HCl or HBr salt disproportionated. Though isostructural, the disproportionation propensity of HBr and HCl salts was quite different. The HCl salt highlighted the important role that volatility of the counterion plays in the physical stability of the formulations. Solution state stability (i.e., in dissolution medium) of salts and cocrystal was also assessed and compared with solid state stability, by determining their solubility at different pH's, and intrinsic dissolution rate.
Asunto(s)
Estabilidad de Medicamentos , Excipientes/química , Preparaciones Farmacéuticas/química , Sales (Química)/química , Agua/química , Cinética , Solubilidad , VolatilizaciónRESUMEN
Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.
Asunto(s)
Isoquinolinas/farmacología , Receptores de Dopamina D1/agonistas , Acetilcolina/metabolismo , Administración Oral , Regulación Alostérica/efectos de los fármacos , Animales , Sitios de Unión , Cristalografía por Rayos X , AMP Cíclico/metabolismo , Células HEK293 , Semivida , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Riñón/efectos de los fármacos , Riñón/metabolismo , Locomoción/efectos de los fármacos , Ratones , Conformación Molecular , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratas , Receptores de Dopamina D1/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Two impurities found in both stressed and aged solid-state formulations of olanzapine have been identified as (Z)-1,3-dihydro-4-(4-methyl-1-piperazinyl)-2-(2-oxopropylidene)-2H-1,5-benzodiazepin-2-one (1) and (Z)-1-[1,2-dihydro-4-(4-methyl-1-piperazinyl)-2-thioxo-3H-1,5-benzodiazepin-3-ylidene]propan-2-one (2). The structures indicate that the two impurities are degradation products resulting from oxidation of the thiophene ring of olanzapine. The impurities were isolated by preparative HPLC from a thermally stressed formulation, and characterized by UV, IR, MS, and NMR. A synthetic preparation of compounds 1 and 2 by reaction of olanzapine with the singlet oxygen mimic 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) is presented. The structure of 2 was also determined by single-crystal X-ray diffraction analysis. A degradation pathway for the formation of 1 and 2 is proposed.
Asunto(s)
Benzodiazepinas/química , Contaminación de Medicamentos , Administración Oral , Benzodiazepinas/administración & dosificación , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Olanzapina , Oxidación-Reducción , Difracción de Rayos XRESUMEN
As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Piridinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Triazoles/farmacología , Administración Oral , Animales , Perros , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Masculino , Piridinas/administración & dosificación , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/síntesis química , Triazoles/farmacocinéticaRESUMEN
Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu3) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4ß-N-linked variants of (1 S,2 S,5 R,6 S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses. From this investigation we identified (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu3 receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu3 revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu2 receptor-dependent behavioral model provides estimates for doses of this compound that would be expected to selectively engage and activate central mGlu3 receptors in vivo.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Animales , Compuestos Bicíclicos con Puentes/farmacocinética , Cristalografía por Rayos X , AMP Cíclico/farmacología , Agonistas de Aminoácidos Excitadores/farmacocinética , Antagonistas de Aminoácidos Excitadores/farmacología , Humanos , Masculino , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fenciclidina/antagonistas & inhibidores , Fenciclidina/farmacología , Unión Proteica , Ratas , Ratas Sprague-DawleyRESUMEN
Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.