RESUMEN
The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
Asunto(s)
Diseño de Fármacos , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Piridinas/administración & dosificación , Piridinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Piridinas/farmacocinética , Células Th17/efectos de los fármacos , Células Th17/metabolismoRESUMEN
Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Dolor/tratamiento farmacológico , Compuestos de Espiro/farmacología , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Compuestos Aza/administración & dosificación , Compuestos Aza/química , Compuestos Aza/farmacología , Compuestos Aza/uso terapéutico , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Ratas , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéuticoRESUMEN
Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k(inact)/K(i) potency values greater than 1500M(-1)s(-1). The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearly distinguished themselves from the other spirocyclic cores on the basis of their superior potency for FAAH. Lead compounds from these two series have suitable FAAH potency and selectivity for additional medicinal chemistry optimization.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Compuestos Aza/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Compuestos de Espiro/farmacología , Compuestos Aza/química , Inhibidores Enzimáticos/química , Modelos Moleculares , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.
RESUMEN
Fatty acid amide hydrolase (FAAH) has attracted significant attention due to its promise as an analgesic target. This has resulted in the discovery of numerous chemical classes as inhibitors of this potential therapeutic target. In this paper we disclose a new series of novel FAAH irreversible azetidine urea inhibitors. In general these compounds illustrate potent activity against the rat FAAH enzyme. Our SAR studies allowed us to optimize this series resulting in the identification of compounds 13 which were potent inhibitors of both human and rat enzyme. This series of compounds illustrated good hydrolase selectivity along with good PK properties.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/química , Azetidinas/química , Inhibidores Enzimáticos/química , Piridazinas/química , Urea/química , Amidohidrolasas/metabolismo , Analgésicos/síntesis química , Analgésicos/farmacocinética , Animales , Azetidinas/síntesis química , Azetidinas/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Piridazinas/síntesis química , Piridazinas/farmacocinética , Ratas , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinéticaRESUMEN
[reaction: see text] A concise stereoselective approach to the spirobicyclic imine fragment of pinnatoxins and pteriatoxins is described. The approach relies on a tandem reaction sequence involving consecutive sigmatropic rearrangements to build the quaternary chiral center at the core of the spirobicyclic ring system.