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1.
ChemMedChem ; 13(10): 988-1003, 2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29485740

RESUMO

Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure-activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.


Assuntos
Anemia/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Nefropatias/complicações , Pirazóis/farmacologia , Triazóis/farmacologia , Anemia/etiologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Camundongos , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Pirazóis/uso terapêutico , Relação Estrutura-Atividade , Triazóis/uso terapêutico
2.
ChemMedChem ; 7(8): 1385-403, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22791416

RESUMO

Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Nefropatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/química , Naftiridinas/química , Receptores de Mineralocorticoides/química , Animais , Sítios de Ligação , Doença Crônica , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Insuficiência Cardíaca/complicações , Humanos , Nefropatias/complicações , Antagonistas de Receptores de Mineralocorticoides/síntese química , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/síntese química , Naftiridinas/uso terapêutico , Potássio/urina , Estrutura Terciária de Proteína , Ratos , Receptores de Mineralocorticoides/metabolismo , Sódio/urina
3.
ChemMedChem ; 1(1): 96-105, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16892341

RESUMO

Inhibition of the metalloprotease ECE-1 may be beneficial for the treatment of coronary heart disease, cancer, renal failure, and urological disorders. A novel class of indole-based ECE inhibitors was identified by high throughput screening. Optimization of the original screening lead structure 6 led to highly potent inhibitors such as 11, which bears a bisaryl amide moiety linked to the indole C2 position through an amide group. Docking of 11 into a model structure of ECE revealed a unique binding mode in which the Zn center of the enzyme is not directly addressed by the inhibitor, but key interactions are suggested for the central amide group. Testing of the lead compound 6 in hypertensive Dahl S rats resulted in a decrease in blood pressure after an initial period in which the blood pressure remained unchanged, most probably the result of ET-1 already present. Indole derivative 6 also displays a cardio-protective effect in a mouse model of acute myocardial infarction after oral administration. The more potent chloropyridine derivative 9 antagonizes big-ET-1-induced increase in blood pressure in rats at intravenous administration of 3 mg kg-1. All ECE inhibitors of the indole class showed high selectivity for ECE over related metalloproteases such as NEP and ACE. Therefore, these compounds might have further potential as drugs for the treatment of coronary heart diseases.


Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Indóis/química , Indóis/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Cromatografia Líquida , Enzimas Conversoras de Endotelina , Inibidores Enzimáticos/farmacocinética , Indóis/farmacocinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 15(19): 4201-5, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16085415

RESUMO

A novel class of indole-based endothelin-converting enzyme (ECE) inhibitors was identified by high throughput screening. We report systematic optimization of this compound class by means of classical and solid-phase chemistry. Optimized compounds with a bisarylamide side chain at the 2-position of the indole skeleton exhibit low-nanomolar activity on ECE.


Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Indóis/síntese química , Metaloendopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Avaliação Pré-Clínica de Medicamentos/métodos , Enzimas Conversoras de Endotelina , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/farmacologia , Concentração Inibidora 50 , Relação Estrutura-Atividade
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