RESUMO
Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.
Assuntos
Ativadores de Enzimas/farmacologia , Músculo Esquelético/enzimologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Animais , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/enzimologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologiaRESUMO
DNA-encoded compound libraries are a widely used small molecule screening technology. One important aim in library design is the coverage of chemical space through structurally diverse molecules. Yet, the chemical reactivity of native DNA barcodes limits the toolbox of reactions for library design. Substituting the chemically vulnerable purines by 7-deazaadenine, which exhibits tautomerization stability similar to natural adenine with respect to the formation of stable Watson-Crick pairs, yielded ligation-competent, amplifiable, and readable DNA barcodes for encoded chemistry with enhanced stability against protic acid- and metal ion-promoted depurination. The barcode stability allowed for straightforward translation of 16 exemplary reactions that included isocyanide multicomponent reactions, acid-promoted Pictet-Spengler and Biginelli reactions, and metal-promoted pyrazole syntheses on controlled pore glass-coupled barcodes for diverse DEL design. The Boc protective group of reaction products offered a convenient handle for encoded compound purification.
RESUMO
BACKGROUND AND PURPOSE: First-generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required. EXPERIMENTAL APPROACH: We report the high-throughput screening (HTS)-based discovery of a second generation of sGC stimulators from a novel imidazo[1,2-a]pyridine lead series. An intense medicinal chemistry programme resulted in the discovery of the sGC stimulator BAY 1165747 (BAY-747). The pharmacokinetic profile of BAY-747 was determined in different species, and it was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension. KEY RESULTS: BAY-747 is a highly potent sGC stimulator in vitro. In addition, BAY-747 showed an excellent pharmacokinetic profile with long half-life and low peak-to-trough ratio. BAY-747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY-747 caused a dose-related and long-lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent decrease. BAY-747 provided additional benefit when dosed on top of losartan, amlodipine or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of rHT, BAY-747 caused a dose-related and long-lasting (>6 h) MAP decrease. CONCLUSION AND IMPLICATIONS: BAY-747 is a potent, orally available sGC stimulator. BAY-747 shows long-acting pharmacodynamic effects with a very low peak-to-trough ratio. BAY-747 could be a treatment alternative for patients with hypertension, especially those not responding to standard-of-care therapy.
Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Hipertensão , Ratos , Animais , Cães , Guanilil Ciclase Solúvel , Hipertensão/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Vasodilatadores/uso terapêuticoRESUMO
Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.
Assuntos
Guanilato Ciclase , Hipertensão , Humanos , Guanilil Ciclase Solúvel/metabolismo , Guanilato Ciclase/metabolismo , Hipertensão/tratamento farmacológico , Vasodilatadores , Piridinas/farmacologia , Piridinas/uso terapêutico , Óxido Nítrico/metabolismoRESUMO
AIMS: The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60-5521, in humans. METHODS: A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60-5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTS: The PBPK approach predicts a greater extent of distribution for BAY 60-5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60-5521 of 51 mg in humans. CONCLUSION: The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60-5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Hidroxiquinolinas/administração & dosagem , Modelos Biológicos , Animais , Biometria , Cães , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidroxiquinolinas/farmacocinética , Hidroxiquinolinas/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Ratos , Ratos WistarRESUMO
DNA-encoded libraries are a prime technology for target-based small molecule screening. Native DNA used as genetic compound barcode is chemically vulnerable under many reaction conditions. DNA barcodes that are composed of pyrimidine nucleobases, 7-deazaadenine, and 7-deaza-8-azaguanine have been investigated for their suitability for encoded chemistry both experimentally and computationally. These four-letter barcodes were readily ligated by T4 ligation, amplifiable by Taq polymerase, and the resultant amplicons were correctly sequenced. Chemical stability profiling showed a superior chemical stability compared to native DNA, though higher susceptibility to depurination than a three-letter code based on pyrimidine DNA and 7-deazaadenine.
RESUMO
Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process.
Assuntos
Benzopiranos/química , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Cromanos/química , Compostos de Espiro/química , Administração Oral , Animais , Benzopiranos/síntese química , Benzopiranos/farmacocinética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/metabolismo , Cromanos/síntese química , Cromanos/farmacocinética , Cães , Humanos , Camundongos , Camundongos Transgênicos , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-AtividadeRESUMO
DNA-encoded libraries designed around heterocyclic scaffolds have proven highly productive in target-based screening. Here, we show the synthesis of imidazopyridines on a controlled pore glass-coupled DNA oligonucleotide for solid phase-initiated encoded library synthesis. The target compounds were synthesized by a variant of the A3 coupling reaction from aminopyridines, alkynes, and aldehydes promoted by copper(I/II) and furnished diverse substituted scaffolds with functionalities for library design. Although proceeding under forcing conditions, it produced minimal DNA damage.
Assuntos
Alcinos/química , Imidazóis/síntese química , Oligonucleotídeos/química , Piridinas/síntese química , Fenômenos Bioquímicos , Cobre/química , Biblioteca Gênica , Imidazóis/química , Estrutura Molecular , Piridinas/química , Técnicas de Síntese em Fase SólidaRESUMO
Introduction: In 2013, riociguat a potent and specific stimulator of the soluble guanylyl cyclase (sGC) was approved as first in class sGC stimulator which reflected a first culmination of intense research and development efforts starting in the mid 1990ies. In the meantime, it turned out that triggering cGMP production by sGC stimulators could have a broad treatment potential. In consequence, various pharmaceutical companies are still very active in identifying novel chemistry for sGC stimulators. After the first generation of sGC stimulators like riociguat or lificiguat, new compound classes with different physicochemical and kinetic profiles were identified, like the sGC stimulators vericiguat or praliciguat.Area covered: Patent literature on sGC stimulators with a focus on recent compounds of the years 2014-2019 as on claimed use and formulations of these compounds. The information was collected from publicly available data sources only (MedLine, EmBase, Chemical Abstracts, Orbit, Dolphin).Expert Opinion: With the recent advancements reported in the patent literature, sGC stimulators might be differentiated due to tissue selectivity or route of application although exhibiting the same molecular mode of action. The indication space of these compounds is potentially very broad and multiple indications in cardiovascular diseases and beyond are under investigation.
Assuntos
Ativadores de Enzimas/farmacologia , Agonistas da Guanilil Ciclase C/farmacologia , Guanilil Ciclase Solúvel/efeitos dos fármacos , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/enzimologia , Desenvolvimento de Medicamentos , Ativadores de Enzimas/química , Agonistas da Guanilil Ciclase C/química , Humanos , Patentes como Assunto , Guanilil Ciclase Solúvel/metabolismoRESUMO
In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifications led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic properties for clinical development.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Hipolipemiantes/química , Quinolinas/química , Animais , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Cães , Humanos , Hipolipemiantes/síntese química , Hipolipemiantes/farmacocinética , Camundongos , Camundongos Transgênicos , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/químicaRESUMO
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Obesidade/tratamento farmacológico , Quinazolinonas/síntese química , Receptores de Grelina/antagonistas & inibidores , Administração Oral , Animais , Ligação Competitiva , Glicemia/análise , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinazolinonas/química , Quinazolinonas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacosRESUMO
Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosineâ A1 receptors (A1 Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1 R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1 R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1 R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1 R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.
Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Dipeptídeos/farmacologia , Cardiopatias/tratamento farmacológico , Pró-Fármacos/farmacologia , Piridinas/farmacologia , Receptor A1 de Adenosina/metabolismo , Agonistas do Receptor A1 de Adenosina/administração & dosagem , Agonistas do Receptor A1 de Adenosina/química , Administração Oral , Animais , Doença Crônica , Dipeptídeos/administração & dosagem , Dipeptídeos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Injeções Intravenosas , Estrutura Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Piridinas/administração & dosagem , Piridinas/química , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Derivatives of the natural product 11-hydroxy-3-[(S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxocin-5-one 1 were studied as novel CETP inhibitors. Compound 2 was identified from HTS as a micromolar inhibitor. The compound suffered from very low stability in plasma. Optimisation by partial synthesis started from 1 and led to low-nanomolar inhibitors with good stability in rat plasma.