RESUMO
Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize absorption for rule of five (Ro5) compounds; beyond rule of five (bRo5) drugs necessitate advanced tools like the experimental measure of exposed polarity (EPSA) and the AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS and EPSA against â¼1000 compounds with human absorption data and â¼10,000 AbbVie tool compounds (â¼1000 proteolysis targeting chimeras or PROTACs, â¼7000 Ro5s, and â¼2000 bRo5s) revealed new patterns of physicochemical trends. We introduced a high-throughput "polarity reduction" descriptor: ETR, the EPSA-to-topological polar surface area (TPSA) ratio, highlights unique bRo5 and PROTAC subsets for specialized drug design strategies for effective absorption. Our methods and guidelines refine drug design by providing innovative in vitro approaches, enhancing physicochemical property optimization, and enabling accurate predictions of intestinal absorption in the complex bRo5 domain.
Assuntos
Descoberta de Drogas , Quimera de Direcionamento de Proteólise , Humanos , Descoberta de Drogas/métodos , Desenho de Fármacos , Absorção Intestinal , ProteóliseRESUMO
CUO246, a novel DNA gyrase/topoisomerase IV inhibitor, is active in vitro against a broad range of Gram-positive, fastidious Gram-negative, and atypical bacterial pathogens and retains activity against quinolone-resistant strains in circulation. The frequency of selection for single step mutants of wild-type S. aureus with reduced susceptibility to CUO246 was <4.64 × 10-9 at 4× and 8× MIC and remained low when using an isogenic QRDR mutant (<5.24 × 10-9 at 4× and 8× MIC). Biochemical assays indicated that CUO246 had potent inhibitory activity against both DNA gyrase (GyrAB) and topoisomerase IV (ParCE). Furthermore, CUO246 showed rapid bactericidal activity in time-kill assays and potent in vivo efficacy against S. aureus in a neutropenic murine thigh infection model. These results suggest that CUO246 may be useful in treating infections by various causative agents of acute skin and skin structure infections, respiratory tract infections, and sexually transmitted infections.
Assuntos
DNA Girase , DNA Topoisomerase IV , Animais , Camundongos , DNA Girase/genética , DNA Topoisomerase IV/genética , Inibidores da Topoisomerase II/farmacologia , DNA Bacteriano , Staphylococcus aureus , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
Interleukin-1 receptor-associated kinase 3 (IRAK3) is a pseudokinase mediator in the human inflammatory pathway, and ablation of its function is associated with enhanced antitumor immunity. Traditionally, pseudokinases have eluded "druggability" and have not been considered tractable targets in the pharmaceutical industry. Herein we disclose a CRISPR/Cas9-mediated knockout of IRAK3 in monocyte-derived dendritic cells that results in an increase in IL-12 production upon lipopolysaccharide (LPS) stimulation. Furthermore, we disclose and characterize Degradomer D-1, which displays selective proteasomal degradation of IRAK3 and reproduces the 1L-12p40 increases observed in the CRISPR/Cas9 knockout.
Assuntos
Citocinas , Quinases Associadas a Receptores de Interleucina-1 , Citocinas/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-12/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/metabolismoRESUMO
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Assuntos
Antivirais/química , Ciclosporina/química , Hepacivirus/fisiologia , Antivirais/síntese química , Antivirais/farmacologia , Ciclização , Ciclosporina/síntese química , Ciclosporina/farmacologia , Dipeptídeos/síntese química , Dipeptídeos/química , Desenho de Fármacos , Quinidina/química , Estereoisomerismo , Replicação Viral/efeitos dos fármacosRESUMO
Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11-13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787.
Assuntos
Antivirais/química , Vírus da Influenza A/enzimologia , Subunidades Proteicas/química , RNA Polimerase Dependente de RNA/química , Antivirais/farmacologia , Sítios de Ligação , Humanos , Vírus da Influenza A/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Subunidades Proteicas/antagonistas & inibidores , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Reversible janus associated kinase (JAK) inhibitors such as tofacitinib and decernotinib block cytokine signaling and are efficacious in treating autoimmune diseases. However, therapeutic doses are limited due to inhibition of other JAK/signal transducer and activator of transcription pathways associated with hematopoiesis, lipid biogenesis, infection, and immune responses. A selective JAK3 inhibitor may have a better therapeutic index; however, until recently, no compounds have been described that maintain JAK3 selectivity in cells, as well as against the kinome, with good physicochemical properties to test the JAK3 hypothesis in vivo. To quantify the biochemical basis for JAK isozyme selectivity, we determined that the apparent Km value for each JAK isozyme ranged from 31.8 to 2.9 µM for JAK1 and JAK3, respectively. To confirm compound activity in cells, we developed a novel enzyme complementation assay that read activity of single JAK isozymes in a cellular context. Reversible JAK3 inhibitors cannot achieve sufficient selectivity against other isozymes in the cellular context due to inherent differences in enzyme ATP Km values. Therefore, we developed irreversible JAK3 compounds that are potent and highly selective in vitro in cells and against the kinome. Compound 2, a potent inhibitor of JAK3 (0.15 nM) was 4300-fold selective for JAK3 over JAK1 in enzyme assays, 67-fold [interleukin (IL)-2 versus IL-6] or 140-fold [IL-2 versus erythropoietin or granulocyte-macrophage colony-stimulating factor (GMCSF)] selective in cellular reporter assays and >35-fold selective in human peripheral blood mononuclear cell assays (IL-7 versus IL-6 or GMCSF). In vivo, selective JAK3 inhibition was sufficient to block the development of inflammation in a rat model of rheumatoid arthritis, while sparing hematopoiesis.
Assuntos
Doenças Autoimunes , Janus Quinase 1 , Janus Quinase 3 , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Humanos , Isoenzimas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/química , Janus Quinase 1/metabolismo , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Monitorização Imunológica/métodos , Inibidores de Proteínas Quinases/farmacologia , RatosRESUMO
The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aß42 lowering maintained in both transgenic mouse and rat.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/farmacocinética , Animais , Disponibilidade Biológica , Camundongos , Camundongos Transgênicos , RatosRESUMO
Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.
Assuntos
Antivirais/química , Antivirais/farmacologia , Ciclofilinas/antagonistas & inibidores , Ciclosporinas/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Técnicas de Química Sintética , Cristalografia por Raios X , Peptidil-Prolil Isomerase F , Ciclofilinas/química , Ciclofilinas/metabolismo , Ciclosporina/química , Ciclosporina/farmacologia , Ciclosporinas/química , Cães , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imunossupressores/química , Imunossupressores/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Fragmentos de Peptídeos/antagonistas & inibidores , Purinas/química , Purinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Purinas/farmacologia , Receptores Notch/metabolismo , Relação Estrutura-AtividadeRESUMO
The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Piperazinas/química , Pirimidinas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/fisiologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologiaRESUMO
A series of 3-aryl-4-hydroxyquinolin-2(1H)-ones with fatty acid synthase inhibitory activity was prepared. Starting from a derivative with an IC(50) = 1.4 microM, SAR studies led to compounds with more than 70-fold increase in potency (IC(50) < 20 nM).
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintases/antagonistas & inibidores , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Inibidores Enzimáticos/química , Ácido Graxo Sintases/metabolismo , Humanos , Hidroxiquinolinas/síntese química , Malonatos/química , Micro-Ondas , Estrutura Molecular , Quinolinas/síntese química , Ratos , Relação Estrutura-AtividadeRESUMO
Small-molecule natural products are presumably often biosynthesized with a view to optimizing their ability to bind to strategic proteins or other biomolecular targets. Although the ultimate setting in which a drug must function may be very different, the use of such natural products as lead compounds can serve as a significant head start in the hunt for new agents of clinical value. Herein we reveal the synergistic relationship between chemical synthesis and drug optimization in the context of our research program around the epothilones: how synthesis led to the discovery of more-potent epothilone derivatives, and discovery inspired the development of new synthetic routes, thus demonstrating the value of target-directed total synthesis in the quest for new substances of material clinical benefit.
Assuntos
Antineoplásicos/química , Epotilonas/química , Animais , Antineoplásicos/farmacologia , Epotilonas/síntese química , Epotilonas/farmacologia , Humanos , Camundongos , Estrutura MolecularRESUMO
We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.
Assuntos
Epotilonas/síntese química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Epotilonas/química , Epotilonas/farmacologia , Humanos , Camundongos , Mycobacterium/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel approach toward the synthesis of the BCD ring system of penitrem D is described. The strategy capitalizes on the fast cyclization rates of aryl radicals into cyclobutenes and allows access to a variety of fused tricyclic structures. Radical/polar crossover reactions of precursors 24-29 promoted by samarium diiodide in the presence of HMPA and acetone allow access to the fully functionalized BCD ring system of penitrem D. The stereochemical implications of these processes are evaluated, and a Pd-mediated cyclization approach toward the penitrems is also introduced.
Assuntos
Ciclobutanos/síntese química , Micotoxinas/síntese química , Paládio/química , Catálise , Ciclização , Radicais Livres/química , Cinética , Modelos Moleculares , Estrutura MolecularRESUMO
There is wide interest in the epothilones, which like the taxoids initiate cytotoxicity through microtubule stabilization. Briefly described is an application of a ring-closing metathesis reaction toward the synthesis of epothilones as carried out in our laboratory. This has led to the discovery of the (E)-9,10-dehydroepothilones as second-generation anticancer drug candidates.
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Epotilonas/química , Epotilonas/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , TaxoidesAssuntos
Antineoplásicos/síntese química , Epotilonas/síntese química , Neoplasias/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Peso Corporal , Ensaios de Seleção de Medicamentos Antitumorais , Epotilonas/farmacologia , Epotilonas/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Modelos Químicos , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Relação Estrutura-Atividade , Células Tumorais CultivadasAssuntos
Epotilonas/química , Epotilonas/síntese química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Epotilonas/farmacologia , Epotilonas/uso terapêutico , Infusões Intravenosas , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Nus , Conformação Molecular , Estrutura Molecular , Transplante de Neoplasias , Fatores de TempoRESUMO
The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Epotilonas/síntese química , Epotilonas/farmacologia , Antineoplásicos/sangue , Antineoplásicos/química , Divisão Celular/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Epotilonas/sangue , Epotilonas/química , Células HCT116 , Humanos , Relação Estrutura-AtividadeRESUMO
[reaction: see text] Radical/polar crossover reactions of derivatives of 1-(2-cyclobutenyl)-2-(2-iodoaryl)ethanones with acetone promoted by samarium diiodide and HMPA provide 1-(1-hydroxy-1-methylethyl)-2,2a,4,8b-tetrahydro-1H-cyclobuta[a]naphthalen-3-one derivatives in about 50% isolated yield. This reaction shows promise for construction of the BCD ring fragment of the penitrems.
Assuntos
Micotoxinas/síntese química , Alcaloides/síntese química , Ciclização , Ciclobutanos/química , Radicais Livres/química , Hidrocarbonetos Cíclicos/síntese química , Iodetos/química , Samário/químicaRESUMO
The disclosure herein describes the synthesis of 10,11-dehydro-13,14-desoxy-27-trifluoro-[17]epothilone B via a stereoselective ring-closing metathesis and provides early biological evaluation data pertinent to this compound. [reaction: see text]