RESUMEN
The total syntheses of aflastatin A and its C3-C48 degradation fragment (6a, R = H) have been accomplished. The syntheses feature several complex diastereoselective fragment couplings, including a Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, a chelate-controlled aldol reaction involving soft enolization with magnesium, and an anti-Felkin-selective boron-mediated oxygenated aldol reaction. Careful comparison of the spectroscopic data for the synthetic C3-C48 degradation fragment to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. Ultimately, the data reported for the naturally derived aflastatin A C3-C48 degradation lactol (6a, R = H) were attributed to its derivative lactol trideuteriomethyl ether (6c, R = CD3). Additionally, the revised absolute configurations of six stereogenic centers (C8, C9, and C28-C31) were confirmed.
Asunto(s)
Aldehídos , Pirrolidinonas , Boro , Estereoisomerismo , Estructura MolecularRESUMEN
Novel prostaglandin E2 receptor 4 (EP4) agonists featuring a pyridone core and an allylic alcohol ω-chain were discovered. These agonists were shown to be selective over EP1, EP2 and EP3. Analogs harboring a 4-carboxylic acid phenethyl α-chain displayed improved potency over those containing an n-heptanoic acid chain. Key SAR relationships were also identified.
Asunto(s)
Propanoles/química , Piridonas/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Humanos , Propanoles/metabolismo , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Piridonas/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-ActividadRESUMEN
There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.
Asunto(s)
Descubrimiento de Drogas , Indazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/síntesis química , Indazoles/química , Células Jurkat , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/química , Sitios de Unión , Cristalografía por Rayos X , Cinética , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/metabolismo , Pirazoles/química , Piridinas/síntesis química , Piridinas/metabolismo , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
Asunto(s)
Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , Farmacorresistencia Viral/efectos de los fármacos , VIH-1/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/química , Triazoles/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Células Cultivadas , Cristalografía por Rayos X , Perros , VIH-1/genética , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Mutación , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/químicaRESUMEN
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Benzotiazoles/síntesis química , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ratones , Modelos Moleculares , Proteínas Tirosina Quinasas/química , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.
Asunto(s)
Amidas/química , Indoles/química , Naftalenos/química , Quinolinas/química , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Compuestos de Sulfonilurea/química , Amidas/síntesis química , Amidas/farmacocinética , Animales , Perros , Evaluación Preclínica de Medicamentos , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-Actividad , Compuestos de Sulfonilurea/síntesis química , Compuestos de Sulfonilurea/farmacocinéticaRESUMEN
Bicyclo[1.1.1]pentanes are effective bioisoteres for aromatic rings, tert-butyl groups, and alkynes. Here we report the first method to synthesize 3-alkylbicyclo[1.1.1]pentan-1-amines directly from [1.1.1]propellane via sequential addition of magnesium amides and alkyl electrophiles. The mild reaction conditions tolerate a variety of important functional groups and enable efficient incorporation of several pharmaceutically relevant amines onto the bicyclo[1.1.1]pentane scaffold. This method's utility is highlighted by its ability to significantly streamline the syntheses of several important bicyclo[1.1.1]pentan-1-amine building blocks.
RESUMEN
A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Quinolinas/química , Quinolinas/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Artritis Experimental/inducido químicamente , Perros , Cobayas , Humanos , Macaca mulatta , Estructura Molecular , Quinolinas/farmacocinética , Ratas , Subtipo EP4 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Sulfonamidas/farmacocinéticaRESUMEN
The enantioselective total synthesis of callipeltoside A is described. Two syntheses of the macrolactone subunit are included: the first relies upon an Ireland-Claisen rearrangement to generate the trisubstituted olefin geometry and the second utilizes an enantioselective vinylogous aldol reaction for this purpose. Enantioselective syntheses of the sugar and chlorocyclopropane side chain fragments are also disclosed. The relative and absolute stereochemistry of this natural product was determined by fragment coupling with the two enantiomers of the side chain fragment.
RESUMEN
NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTßR-dependent p52 translocation and transcription of NF-κB2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Moleculares , Conformación Proteica , Proteínas Serina-Treonina Quinasas/química , Quinasa de Factor Nuclear kappa BRESUMEN
Inhibition of inducible T-cell kinase (ITK), a nonreceptor tyrosine kinase, may represent a novel treatment for allergic asthma. In our previous reports, we described the discovery of sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as novel ITK inhibitors and how computational tools such as dihedral scans and docking were used to support this process. X-ray crystallography and modeling were applied to provide essential insight into ITK-ligand interactions. However, "visual inspection" traditionally used for the rationalization of protein-ligand affinity cannot always explain the full complexity of the molecular interactions. The fragment molecular orbital (FMO) quantum-mechanical (QM) method provides a complete list of the interactions formed between the ligand and protein that are often omitted from traditional structure-based descriptions. FMO methodology was successfully used as part of a rational structure-based drug design effort to improve the ITK potency of high-throughput screening hits, ultimately delivering ligands with potency in the subnanomolar range.
Asunto(s)
Interleucina-2/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Benzotiazoles/química , Cristalografía por Rayos X , Diseño de Fármacos , Inducción Enzimática , Indazoles/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/biosíntesis , Piridinas/química , Teoría CuánticaRESUMEN
[reaction: see text]. Facial selectivity in the addition of boron enolates of alpha-oxygenated ketones to anti-disposed alpha,beta-bisalkoxy aldehydes is controlled by the aldehyde vicinal diol protecting group. Protection of the diol as an acetonide results in the exclusive formation of the anti-syn-anti stereoarray found in the C(33)-C(36) region of aflastatin A.
Asunto(s)
Compuestos de Boro/síntesis química , Compuestos de Boro/química , Estructura Molecular , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Estereoisomerismo , Streptomyces/químicaRESUMEN
[reaction: see text]. The C(8)-C(18) ethyl ketone and C(19)-C(28) aldehyde aflastatin A fragments were synthesized and coupled using a diastereoselective anti aldol reaction. This adduct was successfully converted into the C(9)-C(27) polyol degradation product of (-)-aflastatin A to confirm the relative and absolute stereochemistry of this region of the natural product.
Asunto(s)
Polímeros/química , Estructura Molecular , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Estereoisomerismo , Streptomyces/químicaRESUMEN
The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.
Asunto(s)
Indazoles/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Citotoxinas/química , Citotoxinas/farmacología , Citotoxinas/toxicidad , Femenino , Humanos , Indazoles/farmacología , Indazoles/toxicidad , Interleucina-13/biosíntesis , Interleucina-2/biosíntesis , Células Jurkat , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Fosforilación , Receptores de Antígenos de Linfocitos T/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , Sulfonas/toxicidad , Sulfóxidos/química , Sulfóxidos/farmacología , Sulfóxidos/toxicidadRESUMEN
Interleukin-2 (IL-2)-inducible T cell kinase (ITK) mediates T cell receptor (TCR) signaling primarily to stimulate the production of cytokines, such as IL-4, IL-5, and IL-13, from T helper 2 (TH2) cells. Compared to wild-type mice, ITK knockout mice are resistant to asthma and exhibit reduced lung inflammation and decreased amounts of TH2-type cytokines in the bronchoalveolar lavage fluid. We found that a small-molecule selective inhibitor of ITK blocked TCR-mediated signaling in cultured TH2 cells, including the tyrosine phosphorylation of phospholipase C-γ1 (PLC-γ1) and the secretion of IL-2 and TH2-type cytokines. Unexpectedly, inhibition of the kinase activity of ITK during or after antigen rechallenge in an ovalbumin-induced mouse model of asthma failed to reduce airway hyperresponsiveness and inflammation. Rather, in mice, pharmacological inhibition of ITK resulted in T cell hyperplasia and the increased production of TH2-type cytokines. Thus, our studies predict that inhibition of the kinase activity of ITK may not be therapeutic in patients with asthma.
Asunto(s)
Asma/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Células Th2/inmunología , Animales , Asma/genética , Asma/patología , Muerte Celular/efectos de los fármacos , Citocinas/genética , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Fosfolipasa C gamma/genética , Fosfolipasa C gamma/inmunología , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/inmunología , Células Th2/patologíaRESUMEN
Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17.
Asunto(s)
Alquinos/síntesis química , Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Pirimidinas/síntesis química , Quinasas p21 Activadas/antagonistas & inhibidores , Alquinos/química , Alquinos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Sitios de Unión , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas , Quinasas p21 Activadas/químicaRESUMEN
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.
Asunto(s)
Indazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Células Jurkat , Cinética , Ratones , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
A one-pot synthesis of benzofurans which utilizes a palladium-catalyzed enolate arylation is described. The process demonstrates broad substrate scope and provides differentially substituted benzofurans in moderate to excellent yields. The utility of the method is further demonstrated by the synthesis of the natural product eupomatenoid 6 in three steps.