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1.
Drug Discov Today ; 27(6): 1560-1574, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35202802

RESUMO

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.


Assuntos
Aniversários e Eventos Especiais , Pesquisa Farmacêutica , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/química
2.
Eur J Med Chem ; 163: 763-778, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576906

RESUMO

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.


Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Ensaios de Triagem em Larga Escala , Receptor A2B de Adenosina/efeitos dos fármacos , Adenosina/metabolismo , Animais , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais , Relação Estrutura-Atividade , Uracila/análogos & derivados
3.
ChemMedChem ; 9(1): 61-6, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24285584

RESUMO

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 0.7 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.


Assuntos
Amidas/química , Hipóxia Celular , Oxidiazóis/química , Pirazóis/química , Administração Oral , Amidas/farmacocinética , Amidas/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meia-Vida , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Injeções Intravenosas , Ratos , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos
4.
Arzneimittelforschung ; 58(2): 71-80, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18412020

RESUMO

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.


Assuntos
Benzoatos/farmacologia , Ativadores de Enzimas/farmacologia , Guanilato Ciclase/metabolismo , Hidrocarbonetos Fluorados/farmacologia , Cirrose Hepática Experimental/enzimologia , Óxido Nítrico/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Intoxicação por Tetracloreto de Carbono/enzimologia , Intoxicação por Tetracloreto de Carbono/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Química Farmacêutica , Colágeno/biossíntese , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Feminino , Guanilato Ciclase/genética , Hidroxiprolina/metabolismo , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/tratamento farmacológico , Cirrose Hepática Experimental/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Soro , Guanilil Ciclase Solúvel , Suínos
5.
Bioorg Med Chem Lett ; 17(22): 6151-4, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17910915

RESUMO

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.


Assuntos
Compostos de Bifenilo/farmacologia , Ciclobutanos/farmacologia , Receptores de Vitronectina/antagonistas & inibidores , Sulfonamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Compostos de Bifenilo/química , Ciclobutanos/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Estrutura Terciária de Proteína , Receptores de Vitronectina/química , Relação Estrutura-Atividade , Sulfonamidas/química
6.
Bioorg Med Chem Lett ; 13(6): 1071-4, 2003 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-12643914

RESUMO

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).


Assuntos
Compostos de Bifenilo/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Compostos de Bifenilo/síntese química , Técnicas de Química Combinatória , Integrina alfaVbeta3/antagonistas & inibidores , Ligantes , Modelos Moleculares , Fenilalanina/química , Relação Estrutura-Atividade , Ureia/síntese química
7.
Bioorg Med Chem Lett ; 12(2): 205-8, 2002 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-11755355

RESUMO

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.


Assuntos
Compostos de Bifenilo/farmacologia , Receptores de Vitronectina/antagonistas & inibidores , Compostos de Bifenilo/química , Técnicas de Química Combinatória , Relação Estrutura-Atividade
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