RESUMEN
The year 2021 marks the 125th anniversary of the Bayer Chemical Research Laboratory in Wuppertal, Germany. A significant number of prominent small-molecule drugs, from Aspirin to Xarelto, have emerged from this research site. In this review, we shed light on historic cornerstones of small-molecule drug research, discussing current and future trends in drug discovery as well as providing a personal outlook on the future of drug research with a focus on small molecules.
Asunto(s)
Aniversarios y Eventos Especiales , Investigación Farmacéutica , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
The A2B adenosine receptor is a G protein-coupled receptor that belongs to the four member family of adenosine receptors: A1, A2A, A2B, A3. While adenosine-mediated A2B receptor signaling attenuates acute inflammation, facilitates tissue adaptation to hypoxia, and induces increased ischemia tolerance under conditions of an acute insult, persistently elevated adenosine levels and A2B receptor signaling are characteristics of a number of chronic disease states. In this report we describe the discovery of certain thienouracils (thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones) as antagonists of the A2B adenosine receptor by high-throughput screening from our corporate substance collection. The structure optimization of the initial screening hits led to BAY-545, an A2B receptor antagonist that was suitable for in vivo testing. The structure optimization work, SAR that was derived from there, as well as the properties of BAY-545 are also described. In vivo efficacy of BAY-545 was demonstrated in two models of lung fibrosis and data is presented.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Ensayos Analíticos de Alto Rendimiento , Receptor de Adenosina A2B/efectos de los fármacos , Adenosina/metabolismo , Animales , Fibrosis Pulmonar/tratamiento farmacológico , Transducción de Señal , Relación Estructura-Actividad , Uracilo/análogos & derivadosRESUMEN
The transcription factors hypoxia-inducible factor-1 and -2 (HIF-1 and HIF-2) orchestrate a multitude of processes that allow tumor cells to survive under conditions of low oxygen and nutrients, and that lead to resistance to some apoptotic pathways and facilitate invasion and metastasis. Therefore, inhibition of transactivation by HIF has become an attractive target in cancer research. Herein we present the results of a cell-based screening approach that led to the discovery of substituted 1H-pyrazole-3-carboxamides. Chemical optimization of the hit class with respect to potency and metabolic stability is described; it resulted in novel 5-(1H-pyrazol-3-yl)-1,2,4-oxadiazoles that inhibit the hypoxia-induced accumulation of HIF-1α and HIF-2α. The HIF inhibitory potency in the screening cell system was improved from IC50 190 to 0.7â nM, and significant parts of the SAR are disclosed. For a key compound, the ability to suppress the hypoxia-induced expression of HIF target genes was studied in A549 human lung adenocarcinoma cells. The same compound shows a favorable pharmacokinetic profile in rats after i.v. and p.o. administration.
Asunto(s)
Amidas/química , Hipoxia de la Célula , Oxadiazoles/química , Pirazoles/química , Administración Oral , Amidas/farmacocinética , Amidas/toxicidad , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Semivida , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inyecciones Intravenosas , Ratas , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacosRESUMEN
UNLABELLED: Liver cirrhosis is a chronic disease with high mortality rate and need for effective pharmacological intervention. The fibrotic remodelling of liver tissue is crucially dependent on hepatic stellate cell activation. Activation of hepatic stellate cells is reduced by an increase in cyclic guanosine monophosphate (cGMP). Stable cGMP analogues also reduce the contractile response of hepatic stellate cells. However, cGMP production is downregulated in the cirrhotic liver due to the reduced activity of the endothelial nitric oxide synthase. OBJECTIVE: Here we report that the novel activator of soluble guanylate cyclase (sGC), BAY 60-2770 (4-({(4-carboxybutyl) [2- (5-fluoro-2-{[4'-(trifluoromethyl) biphenyl-4-yl]methoxy}phenyl)ethyl] amino}methyl)benzoic acid), which increases the activity of sGC in a nitric oxide-independent manner, attenuates liver fibrosis in two rat models. METHODS: The compound was studied in the pig serum model and the carbon tetrachloride model. Fibrosis was assessed by estimating the increase in fibrous collagen by micromorphometry of histological sections stained with Sirius Red/Fast Green and by measuring total hepatic collagen. RESULTS: BAY 60-2770, on a recombinant sGC reporter cell line, stimulated the luminescence signals with an EC50 value of 5.4 +/- 1.2 nmol/L. In the presence of [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 pmol/L) the EC50 was shifted to 0.39 +/- 0.11 nmol/L. In both fibrosis models, once daily oral administration of BAY 60-2770 concomittantly with the fibrotic stimulus prevented 60-75% of fibrosis, the lowest effective dose being 0.1 mg/kg in the pig serum model and 0.3 mg/kg in the carbon tetrachloride model. The treatment was well tolerated by all animals. The doses used were devoid of any significant influence on systemic blood pressure. CONCLUSION: Nitric oxide-independent activation of sGC might be an innovative therapeutic approach for the treatment of liver fibrosis of necro-inflammatory and immunological origin.
Asunto(s)
Benzoatos/farmacología , Activadores de Enzimas/farmacología , Guanilato Ciclasa/metabolismo , Hidrocarburos Fluorados/farmacología , Cirrosis Hepática Experimental/enzimología , Óxido Nítrico/fisiología , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Intoxicación por Tetracloruro de Carbono/tratamiento farmacológico , Intoxicación por Tetracloruro de Carbono/enzimología , Intoxicación por Tetracloruro de Carbono/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Química Farmacéutica , Colágeno/biosíntesis , Progresión de la Enfermedad , Activación Enzimática/efectos de los fármacos , Femenino , Guanilato Ciclasa/genética , Hidroxiprolina/metabolismo , Hígado/enzimología , Hígado/patología , Cirrosis Hepática Experimental/tratamiento farmacológico , Cirrosis Hepática Experimental/patología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/genética , Suero , Guanilil Ciclasa Soluble , PorcinosRESUMEN
Vitronectin receptor (alpha(V)beta(3)) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the alpha(V)beta(3)/ligand interaction. Squaric acid amide 10 is a subnanomolar alpha(V)beta(3) antagonist with improved potency on human smooth muscle cell migration.
Asunto(s)
Compuestos de Bifenilo/farmacología , Ciclobutanos/farmacología , Receptores de Vitronectina/antagonistas & inhibidores , Sulfonamidas/farmacología , Sitios de Unión/efectos de los fármacos , Compuestos de Bifenilo/química , Ciclobutanos/química , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Estructura Terciaria de Proteína , Receptores de Vitronectina/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated as a mechanism for the treatment of restenosis following balloon angioplasty. In this work we present results from screening of a focused combinatorial library based on a biphenyl moiety. Our SAR studies led to the identification of compounds with subnanomolar activity, selectivity towards the related GPIIbIIIa receptor and functional activity on human smooth muscle cell migration.
Asunto(s)
Compuestos de Bifenilo/farmacología , Receptores de Vitronectina/antagonistas & inhibidores , Compuestos de Bifenilo/química , Técnicas Químicas Combinatorias , Relación Estructura-ActividadRESUMEN
Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3).