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1.
J Med Chem ; 65(24): 16420-16431, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36475653

RESUMO

Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases.


Assuntos
GMP Cíclico , Insuficiência Cardíaca , Camundongos , Animais , GMP Cíclico/metabolismo , Ensaios de Triagem em Larga Escala , 3',5'-AMP Cíclico Fosfodiesterases
2.
J Med Chem ; 63(20): 11639-11662, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32969660

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure-activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvements-including increase of the relative oral bioavailability Frel from 3 to ≥100%-led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 (46) represents-to the best of our knowledge-the first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Quinolinas/síntese química , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Estrutura Molecular , Quinolinas/química , Quinolinas/uso terapêutico , Ratos , Ratos Wistar , Relação Estrutura-Atividade
3.
ChemMedChem ; 11(2): 199-206, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26333652

RESUMO

Human neutrophil elastase (HNE) is a key driver of inflammation in many cardiopulmonary and systemic inflammatory and autoimmune conditions. Overshooting high HNE activity is the consequence of a disrupted protease-antiprotease balance. Accordingly, there has been an intensive search for potent and selective HNE inhibitors with suitable pharmacokinetics that would allowing oral administration in patients. Based on the chemical probe BAY-678 and the clinical candidate BAY 85-8501 we explored further ring topologies along the equator of the parent pyrimidinone lead series. Novel ring systems were annulated in the east, yielding imidazolo-, triazolo-, and tetrazolopyrimidines in order to ensure additional inhibitor-HNE contacts beyond the S1 and the S2 pocket of HNE. The western annulation of pyridazines led to the polar pyrimidopyridazine BAY-8040, which combines excellent potency and selectivity with a promising pharmacokinetic profile. In vivo efficacy with regard to decreasing cardiac remodeling and amelioration of cardiac function was shown in a monocrotaline-induced rat model for pulmonary arterial hypertension. This demonstrated in vivo proof of concept in animals.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Elastase de Leucócito/antagonistas & inibidores , Proteínas Secretadas Inibidoras de Proteinases/química , Proteínas Secretadas Inibidoras de Proteinases/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Hipertensão Pulmonar/metabolismo , Elastase de Leucócito/metabolismo , Modelos Moleculares , Estrutura Molecular , Proteínas Secretadas Inibidoras de Proteinases/síntese química , Piridazinas/síntese química , Pirimidinas/síntese química , Ratos , Relação Estrutura-Atividade
4.
ChemMedChem ; 10(7): 1163-73, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26083237

RESUMO

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.


Assuntos
Congelamento , Elastase de Leucócito/antagonistas & inibidores , Pneumopatias/enzimologia , Proteínas Secretadas Inibidoras de Proteinases/farmacologia , Pirimidinonas/farmacologia , Sulfonas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Elastase de Leucócito/metabolismo , Conformação Molecular , Proteínas Secretadas Inibidoras de Proteinases/química , Pirimidinonas/química , Relação Estrutura-Atividade , Sulfonas/química
5.
ChemMedChem ; 3(4): 619-26, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18246567

RESUMO

Natural products have provided the majority of lead structures for marketed antibacterials. In addition, they are biological guide principles to new therapies. Nevertheless, numerous "old" classes of antibiotics such as the longicatenamycins have never been explored by chemical postevolution. Longicatenamycin A is the first defined longicatenamycin congener that has been totally synthesized and tested in pure form. This venture required the de novo syntheses of the non-proteinogenic amino acids (2S,3R)-beta-hydroxyglutamic acid (HyGlu), 5-chloro-D-tryptophan (D-ClTrp), and (S)-2-amino-6-methylheptanoic acid (hhLeu). In the key step, the sensitive HyGlu building block was coupled as a pentafluorophenyl active ester to the unprotected H-D-ClTrp-Glu-hhLeu-D-Val-D-(Cbz)Orn-OH fragment. This first total synthesis of longicatenamycin A provided new congeners of the natural product (deacetyllongicatenamycin, dechlorolongicatenamycin, and longicatenamycin-A-amide).


Assuntos
Antibacterianos/síntese química , Peptídeos/síntese química , Ciclização , Modelos Moleculares , Peptídeos/química , Peptídeos/farmacologia , Relação Estrutura-Atividade
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