RESUMEN
Glucocorticoid receptor modulators (GRM) are the first-line treatment for many immune diseases, but unwanted side effects restrict chronic dosing. However, targeted delivery of a GRM payload via an immunology antibody-drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to unwanted side effects. We initiated our α-TNF-GRM ADC project focusing on identifying the optimal payload and a linker that afforded stable attachment to both the payload and antibody, resulting in the identification of the synthetically accessible maleimide-Gly-Ala-Ala linker. DAR 4 purified ADCs were shown to be more efficacious in a mouse contact hypersensitivity model than the parent α-TNF antibody. Analysis of P1NP and corticosterone biomarkers showed there was a sufficient therapeutic window between efficacy and unwanted effects. In a chronic mouse arthritis model, α-TNF-GRM ADCs were more efficacious than both the parent α-TNF mAb and an isotype control bearing the same GRM payload.
Asunto(s)
Antineoplásicos , Inmunoconjugados , Animales , Anticuerpos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Receptores de GlucocorticoidesRESUMEN
Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.
Asunto(s)
Productos Biológicos/síntesis química , Diseño de Fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Regulación Alostérica , Animales , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Ligandos , Ratones , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Interest in sphingosine-1-phosphate (S1P)(1) receptor agonists has increased steadily since the discovery that the mechanism of action of fingolimod (FTY-720)-induced lymphopenia is linked to the S1P GPCR family. Fingolimod is an agonist at four out of the five S1P family receptors. Adoptive cell transfer experiments and selective S1P(1) receptor agonists provided evidence that the S1P(1) receptor is the main target responsible for trapping lymphocytes in secondary lymphoid tissue. This readily accessible, translatable biomarker has been correlated with efficacy in rodent models of immune disease. Novartis AG filed for regulatory approval for fingolimod in the US and EU for the treatment of multiple sclerosis in December 2009. In addition, more selective compounds targeting S1P receptors from several companies have entered clinical trials. These compounds can be categorized into two classes of S1P(1) receptor agonists: amino alcohol prodrugs and second-generation direct agonists. This review focuses on the development of these compounds and the role of S1P receptor family selectivity.
Asunto(s)
Enfermedades del Sistema Inmune/tratamiento farmacológico , Lisofosfolípidos/uso terapéutico , Proteínas del Tejido Nervioso/agonistas , Proteínas de Unión al ARN/agonistas , Esfingosina/análogos & derivados , Animales , Ensayos Clínicos como Asunto , Humanos , Enfermedades del Sistema Inmune/metabolismo , Lisofosfolípidos/química , Lisofosfolípidos/farmacología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Preparaciones Farmacéuticas , Proteínas de Unión al ARN/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Esfingosina/química , Esfingosina/farmacología , Esfingosina/uso terapéuticoRESUMEN
Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.
Asunto(s)
Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Oligopéptidos/química , Oligopéptidos/farmacología , Receptores de Glucagón/agonistas , Secuencia de Aminoácidos , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Oligopéptidos/síntesis química , Oligopéptidos/farmacocinética , Conformación ProteicaRESUMEN
The individual isomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate are useful intermediates for the synthesis of S1P1 receptor agonists. Herein we describe a scalable synthesis and isolation of each of the four stereoisomers of this compound in gram quantities with >98% ee and de. The utility of this approach is demonstrated by the synthesis of ((1R,3R)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol in 7 steps, 11% overall yield, and >98% ee and de.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ciclopentanos/síntesis química , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Ácidos Carboxílicos/química , Ciclopentanos/química , Estructura Molecular , Receptores de Lisoesfingolípidos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization.
Asunto(s)
Amidas/farmacología , Bencimidazoles/farmacología , Quinolinas/farmacología , Receptores CXCR3/antagonistas & inhibidores , Amidas/química , Animales , Bencimidazoles/síntesis química , Sitios de Unión , Células CHO/efectos de los fármacos , Cricetinae , Cricetulus , Humanos , Modelos Químicos , Quinolinas/química , Ensayo de Unión Radioligante , Receptores CXCR3/metabolismo , Relación Estructura-ActividadRESUMEN
High-throughput screening identified a low molecular weight antagonist of CXCR3 displaying micromolar activity in a membrane filtration-binding assay. Systematic modification of the benzimidazole core and tethered acetophenone moiety established tractable SAR of analogs with improved physicochemical properties and sub-micromolar activity across both human and murine receptors.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Receptores CXCR3/antagonistas & inhibidores , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino acid derivatives were identified as very potent motilin receptor agonists. Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660 nM) was found to improve in vitro potency approximately 3000-fold, resulting in compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of 0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the binding assay. In addition, compound 11A was shown to have a significantly reduced tendency to cause receptor desensitization as compared with the motilin receptor agonist ABT-229.