RESUMEN
Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout db/db mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (P<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, α-smooth muscle actin, connective tissue growth factor, collagen I, and TGF-ß; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, n=4; at 20 weeks: 364±18 with vehicle, n=7, and 536±12 with LPAR inhibition, n=7; P<0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.
Asunto(s)
Nefropatías Diabéticas/prevención & control , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Animales , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/etiología , Modelos Animales de Enfermedad , Ratones , Receptores del Ácido Lisofosfatídico/fisiologíaRESUMEN
The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).
Asunto(s)
Descubrimiento de Drogas , Fibrosis Pulmonar/tratamiento farmacológico , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Fibrosis Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/metabolismo , Relación Estructura-ActividadRESUMEN
Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.
Asunto(s)
Aminas/química , Aminopiridinas/síntesis química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Aminopiridinas/química , Aminopiridinas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
[reaction: see text] New methods for the palladium-catalyzed cyanation of aryl and heteroaryl chlorides have been developed, featuring sterically demanding, electron-rich phosphines. Highly challenging electron-rich aryl chlorides, in addition to electron-neutral and electron-deficient substrates, as well as nitrogen- and sulfur-containing heteroaryl chlorides can all undergo efficient cyanation under relatively mild conditions using readily available materials. In terms of substrate scope and temperature, these methods compare very favorably with the state-of-the-art cyanations of aryl chlorides.
Asunto(s)
Cloruros/química , Cianuros/química , Paladio/química , Compuestos de Anilina/química , Catálisis , Cloruros/síntesis química , Ligandos , Estructura MolecularRESUMEN
Using a high-throughput screening strategy, a series of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones was identified that inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated phosphorylation of a protein substrate with IC(50)s in the low micromolar range. On the basis of preliminary structure-activity relationships (SAR), a model was proposed in which these inhibitors occupy the ATP-binding site of the enzyme, forming critical hydrogen bonds to the same residue (Val96) to which the amino group in ATP is presumed to bind. X-ray diffraction studies on a later derivative bound to CDK2 support this binding mode. Iterative cycles of synthesis and screening lead to a novel series of potent, CDK2-selective 6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the meta-position on the 6-arylmethyl group resulted in approximately 100-fold increases in CDK4 affinity, giving ligands that were equipotent inhibitors of CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI HCT116 and other cell lines. The potency of these antiproliferative effects is enhanced in anilide derivatives and translates into tumor growth inhibition in a mouse xenograft model.
Asunto(s)
Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Células Cultivadas , Cristalografía por Rayos X , Ciclina D1/antagonistas & inhibidores , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Fosforilación , Proteínas Proto-Oncogénicas/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
In a high-throughput screening effort, a series of tetrahydroisoquinolines was identified as modest inhibitors of human Eg5. A medicinal chemistry optimization effort led to the identification of R-4-(3-hydroxyphenyl)-N,N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (32a) as a potent inhibitor of human Eg5 (ATPase IC50 104 nM) with good anti-proliferative activity in A2780 cells (IC50 234 nM).
Asunto(s)
Antineoplásicos/farmacología , Isoquinolinas/síntesis química , Cinesinas/antagonistas & inhibidores , Mitosis/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Adenosina Trifosfatasas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Isoquinolinas/farmacología , Estructura Molecular , Tetrahidroisoquinolinas/síntesis química , Células Tumorales CultivadasRESUMEN
A series of P1/P1' substituted cyclic urea analogues were prepared in an attempt to increase the intra-cellular antiviral potency of the nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851. The effect of alkyl substitution of the P1/P1' residues on cellular antiviral potency, protein binding, resistance profile and pharmacokinetics are described.