RESUMEN
We identified and explored the structure-activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the cost-prohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings.
Asunto(s)
Antivirales/farmacología , Arenavirus/efectos de los fármacos , Descubrimiento de Drogas , Compuestos Heterocíclicos/farmacología , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Arenavirus/metabolismo , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Proteínas del Envoltorio Viral/metabolismoRESUMEN
Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R1 and R4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R6 substituents and iterative R1, R4 and R6 substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility.
Asunto(s)
Antivirales/farmacología , Arenavirus/efectos de los fármacos , Piperazinas/farmacología , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Arenavirus/metabolismo , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Relación Estructura-Actividad , Proteínas del Envoltorio Viral/metabolismoRESUMEN
Lead optimization efforts that employed structure base drug design and physicochemical property based optimization leading to the discovery of a novel series of 4-methylpyrido pyrimidinone (MPP) are discussed. Synthesis and profile of 1, a PI3Kα/mTOR dual inhibitor, is highlighted.
Asunto(s)
Diseño de Fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Piridonas/química , Pirimidinas/química , Pirimidinonas/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Sitios de Unión , Cristalografía por Rayos X , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Piridonas/síntesis química , Piridonas/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Pirrolidinas/química , Ratas , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the ß-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.
Asunto(s)
Inhibidores de Integrasa VIH/química , Integrasa de VIH/química , VIH-1/enzimología , Ácidos Hidroxámicos/química , Indoles/química , Administración Oral , Animales , Perros , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/toxicidad , Semivida , Hepatocitos/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/toxicidad , Relación Estructura-ActividadRESUMEN
BRAF is among the most frequently mutated oncogenes in human cancers. Multiple small molecule BRAF kinase inhibitors have been approved for treating melanoma carrying BRAF-V600 mutations. However, the benefits of BRAF kinase inhibitors are generally short-lived. Small molecule-mediated targeted protein degradation has recently emerged as a novel pharmaceutical strategy to remove disease proteins through hijacking the cellular ubiquitin proteasome system (UPS). In this study, we developed thalidomide-based heterobifunctional compounds that induced selective degradation of BRAF-V600E, but not the wild-type BRAF. Downregulation of BRAF-V600E suppressed the MEK/ERK kinase cascade in melanoma cells and impaired cell growth in culture. Abolishing the interaction between degraders and cereblon or blocking the UPS significantly impaired the activities of these degraders, validating a mechanistic role of UPS in mediating targeted degradation of BRAF-V600E. These findings highlight a new approach to modulate the functions of oncogenic BRAF mutants and provide a framework to treat BRAF-dependent human cancers.
Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Vemurafenib/química , Vemurafenib/metabolismo , Vemurafenib/farmacologíaRESUMEN
We report compounds 5 (CG416) and 6 (CG428) as two first-in-class tropomyosin receptor kinase (TRK) degraders that target the intracellular kinase domain of TRK. Degraders 5 and 6 reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling at sub-nanomolar concentrations. Both degraders also degraded human wild-type TRKA with similar potency. Interestingly, both degraders, especially 6, showed selectivity for the degradation of endogenous TPM3-TRKA over ectopically expressed ATP/GTP binding protein-like 4 (AGBL4)-TRKB or ETS variant transcription factor 6 (ETV6)-TRKC fusion proteins in KM12 cells. Global proteomic profiling assays demonstrated that 5 is highly selective for the intended target. TPM3-TRKA protein degradation induced by 5 and 6 was further confirmed to be mediated through cereblon and the ubiquitin-proteasome system. Compared with the parental TRK kinase inhibitor, both degraders exhibited higher potency for inhibiting growth of KM12 cells. Moreover, both 5 and 6 showed good plasma exposure levels in mice. Therefore, 5 and 6 are valuable chemical tool compounds for investigating the in vivo function of TRK fusion during tumorigenesis. Our study also paves the way for pharmacological degradation of TRK.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Talidomida/análogos & derivados , Talidomida/farmacología , Animales , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Masculino , Ratones Endogámicos ICR , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteolisis/efectos de los fármacos , Piridazinas/síntesis química , Piridazinas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor trkA/antagonistas & inhibidores , Receptor trkA/metabolismo , Receptor trkB/antagonistas & inhibidores , Receptor trkB/metabolismo , Receptor trkC/antagonistas & inhibidores , Receptor trkC/metabolismo , Relación Estructura-Actividad , Talidomida/farmacocinética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
We identified and explored the structure-activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC50 values) of â¼10-15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC50 activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates.
RESUMEN
rac-Benzyl 3-oxohexa-hydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxyl-ate was separated by chiral chromatography, and one of the enanti-omers ([α](22) (D) = +10°) was hydrogenated in the presence of Pd/C in methanol, producing octa-hydro-3H-pyrrolo[3,4-c]pyridin-3-one. The latter was reacted with (2R)-3,3,3-trifluoro-2-meth-oxy-2-phenyl-propanoyl chloride [(R)-(-)-Mosher acid chloride], giving rise to the title compound, C(17)H(19)F(3)N(2)O(3)·H(2)O. The present structure established the absolute configuration of the pyrrolopiperidine fragment based on the known configuration of the (R)-Mosher acid chloride. The piperidine ring has a somewhat distorted chair conformation and is cis-fused with the five-membered envelope-shaped ring; the plane of the exocyclic amide bond is approximately orthogonal to the plane of the phenyl ring, making a dihedral angle of 82.31â (3)°. The water mol-ecule acts as an acceptor to the proton of the amino group in an N-Hâ¯O inter-action, and as a double proton donor in O-Hâ¯O hydrogen bonds, generating infinite bands along the a axis.
RESUMEN
A weak human glucagon receptor antagonist with an IC50 of 7 microM was initially found by screening of libraries originally targeted to mimic the binding of the glucagon-like peptide (GLP-1) hormone to its receptor. Optimization of this hit for binding affinity for the glucagon receptor led to ligands with affinity in the nanomolar range. In addition to receptor binding, optimization efforts were made to stabilize the molecules against fast metabolic turnover. A potent antagonist of the human human glucagon receptor was obtained that had 17% oral availability in rats with a plasma half-life of 90 min. The major metabolites of this lead were identified and used to further optimize this series with respect to pharmacokinetic properties. This final optimization led to a potent glucagon antagonist that was orally available in rats and dogs and was efficacious in lowering blood glucose levels in a diabetic animal model.
Asunto(s)
Hipoglucemiantes/síntesis química , Receptores de Glucagón/antagonistas & inhibidores , beta-Alanina/análogos & derivados , beta-Alanina/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Humanos , Hipoglucemiantes/farmacología , Ratones , Ratones Obesos , Ratas , Relación Estructura-Actividad , beta-Alanina/farmacologíaRESUMEN
Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 430 pM, K(B) = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K(i) = 14 nM). This compound was orally available in dogs (F(po) = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.
Asunto(s)
Hidrazinas/síntesis química , Indoles/síntesis química , Receptores de Glucagón/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Células Cultivadas , Perros , Glucagón/sangre , Glucosa/biosíntesis , Hepatocitos/metabolismo , Humanos , Hidrazinas/farmacocinética , Hidrazinas/farmacología , Hiperglucemia/metabolismo , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Naftiridinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Células Cultivadas , Perros , Diseño de Fármacos , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , VIH-1/enzimología , Hepatocitos/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Hígado/metabolismo , Conformación Molecular , Naftiridinas/farmacocinética , Naftiridinas/farmacología , Relación Estructura-ActividadRESUMEN
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.
Asunto(s)
Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/enzimología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores de Integrasa VIH/síntesis química , VIH-1/efectos de los fármacos , Ácidos Hidroxámicos/síntesis química , Concentración 50 Inhibidora , Ligandos , Magnesio/metabolismo , Picolinas/químicaRESUMEN
A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats.