RESUMO
The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.
Assuntos
Antivirais , Inibidores de Protease de Coronavírus , Furanos , Antivirais/química , Antivirais/farmacologia , Lactamas , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , SARS-CoV-2 , Furanos/química , Inibidores de Protease de Coronavírus/químicaRESUMO
A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
Assuntos
Pirrolidinas/química , Receptores de Progesterona/agonistas , Animais , Sítios de Ligação , Carbamatos/química , Cristalografia por Raios X , Canal de Potássio ERG1 , Endometriose/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Humanos , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Receptores de Progesterona/metabolismo , Sulfonamidas/químicaRESUMO
Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold hopping approach, which relied on use of an internal H-bond to replace a saturated heterocyclic ring. Optimization of the lead through investigation of both aryl regions revealed approaches to increase potency through substituents believed to enhance separate intramolecular and intermolecular H-bond interactions. A proposed internal H-bond between the amine and neighboring benzenesulfonamide was stabilized by electronically modulating the benzenesulfonamide. In the aryl ether moiety, substituents para to the nitrile demonstrated an electronic effect on TRPV4 recognition. Finally, the acyclic amines inactivated CYP3A4 and this liability was addressed by modifications that sterically preclude formation of a putative metabolic intermediate complex to deliver advanced TRPV4 antagonists as leads for discovery of novel medicines.
Assuntos
Diaminas/química , Sulfonamidas/química , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Citocromo P-450 CYP3A/metabolismo , Diaminas/síntese química , Diaminas/metabolismo , Diaminas/farmacocinética , Desenho de Fármacos , Humanos , Ligação de Hidrogênio/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Canais de Cátion TRPV/química , Canais de Cátion TRPV/metabolismoRESUMO
Two classes of amino acid-derived heterocyclic progesterone receptor ligands were developed to address the metabolic issues posed by the dimethyl amide functionality of the lead compound (1). The tetrazole-derived ligands behaved as potent partial agonists, while the 1,2,4-triazole ligands behaved as potent full agonists.
Assuntos
Receptores de Progesterona/agonistas , Tetrazóis/síntese química , Aminoácidos/química , Animais , Ratos , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Glucocorticoides/química , Ácido Glucurônico/química , Proteínas Imediatamente Precoces/química , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Inibidores de Proteínas Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Ratos , Relação Estrutura-AtividadeRESUMO
GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.
Assuntos
Pirrolidinas/química , Sulfonamidas/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Animais , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Pirrolidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.
RESUMO
Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we show that the serum and glucocorticoid-regulated kinase 1 (SGK1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional serum- and glucocorticoid-regulated kinase 1 (SGK1) protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNA interference-mediated knockdown of SGK1 expression attenuates the androgen-mediated growth of the prostate cancer cell line LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small-molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR is likely to have therapeutic utility in prostate cancer.
Assuntos
Proteínas Imediatamente Precoces/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Benzoatos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Proteínas Imediatamente Precoces/biossíntese , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Masculino , Metribolona/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Receptores Androgênicos/metabolismo , Regulação para CimaRESUMO
This paper describes the synthesis and biological evaluation of a series of straight chain analogs of a compound (1) that was previously synthesized in our research program. These compounds, which are T-type calcium channel antagonists, exhibits potent anti-proliferative activity against a variety of cancer cells. A structure-activity relationship of these analogs against a variety of cancer cells has provided insight into a logical pharmacophore for this series of compounds. Furthermore, this series of compounds has presented itself as a set of novel, concentration dependent, dual action agonists/antagonists for the T-type calcium channel.
Assuntos
Agonistas dos Canais de Cálcio/química , Agonistas dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Relação Estrutura-AtividadeRESUMO
This paper describes the synthesis of several novel T-type calcium channel antagonists that inhibit calcium influx into the cell, which in turn regulates unknown aspects of the cell cycle pathway that are responsible for cellular proliferation. A library of compounds was synthesized and a brief structure activity relationship will be described. From these studies we have identified a compound (1) that displays anti-proliferative activity in the low micromolar range across a variety of cancer cell lines.