RESUMO
The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.
Assuntos
Ácido Graxo Sintases/antagonistas & inibidores , Piperazinas/química , Administração Oral , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ácido Graxo Sintases/metabolismo , Meia-Vida , Humanos , Malonil Coenzima A/metabolismo , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piperazinas/farmacologia , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-AtividadeRESUMO
A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound FT001, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).
RESUMO
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Éteres Fenílicos/farmacologia , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Linhagem Celular , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/síntese química , Inibidores do Citocromo P-450 CYP2C9/química , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/química , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
The total syntheses of 12-epoxyobtusallene IV, 12-epoxyobtusallene II, obtusallene X, marilzabicycloallene C, and marilzabicycloallene D as halogenated C15-acetogenin 12-membered bicyclic and tricyclic ether bromoallene-containing marine metabolites from Laurencia species are described. Two enantiomerically pure C4-epimeric dioxabicyclo[8.2.1]tridecenes were synthesized by E-selective ring-closing metathesis where their absolute stereochemistry was previously set via catalytic asymmetric homoallylic epoxidation and elaborated via regioselective epoxide-ring opening and diastereoselective bromoetherification. Epimeric face-selective oxidation of their Δ12,13 olefins followed by bromoallene installation allowed access to the oppositely configured 12,13-epoxides of 12-epoxyobtusallene II and 12-epoxyobtusallene IV. Subsequent exploration of their putative biomimetic oxonium ion formation-fragmentations reactions revealed diastereodivergent pathways giving marilzabicycloallene C and obtusallene X, respectively. The original configurations of the substrates evidently control oxonium ion formation and their subsequent preferred mode of fragmentation by nucleophilic attack at C9 or C12. Quantum modeling of this stereoselectivity at the ωB97X-D/Def2-TZVPPD/SCRF = methanol level revealed that in addition to direction resulting from hydrogen bonding, the dipole moment of the ion-pair transition state is an important factor. Marilzabicycloallene D as a pentahalogenated 12-membered bicyclic ether bromoallene was synthesized by a face-selective chloronium ion initiated oxonium ion formation-fragmentation process followed by subsequent bromoallene installation.
RESUMO
This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Compostos Azabicíclicos/síntese química , Compostos de Metilureia/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirazóis/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Administração por Inalação , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Compostos Azabicíclicos/farmacocinética , Compostos Azabicíclicos/farmacologia , Sítios de Ligação , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Cães , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Cinética , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Compostos de Metilureia/farmacocinética , Compostos de Metilureia/farmacologia , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Solubilidade , Ressonância de Plasmônio de Superfície , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.
Assuntos
Corticosteroides/síntese química , Corticosteroides/farmacocinética , Antiasmáticos/síntese química , Antiasmáticos/farmacocinética , Asma/tratamento farmacológico , Desenho de Fármacos , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/farmacologia , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/uso terapêutico , Androstadienos/química , Androstadienos/farmacologia , Animais , Antiasmáticos/administração & dosagem , Antiasmáticos/farmacologia , Asma/epidemiologia , Asma/fisiopatologia , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Inaladores de Pó Seco , Fluticasona , Hepatócitos , Humanos , Fígado , Pulmão , Microssomos Hepáticos , Neutrófilos/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/sangueRESUMO
p38 has been an intensely studied therapeutic target in the pharmaceutical industry. With more than 20 compounds entering human trials, none have progressed beyond Phase II to the best of our knowledge. The transient efficacy seen in many of the Phase II trials has raised some concerns for the future potential of this target, particularly in rheumatoid arthritis. With this caveat, there is good evidence for p38 inhibition to be efficacious in chronic obstructive pulmonary disease and there are now several oral compounds currently in development for this disease, with encouraging data beginning to emerge. With an inhaled agent likely to improve the therapeutic window between efficacy and some of the common adverse events observed with oral p38 inhibitors it would seem a sensible approach to take for a disease of the lung. This review will highlight the potential for an inhaled p38 inhibitor in chronic obstructive pulmonary disease, as well as some of the design principles that are important to consider when developing an inhaled kinase inhibitor.
Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Administração por Inalação , Humanos , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
We report the use of fragment screening and fragment based drug design to develop a PI3γ kinase fragment hit into a lead. Initial fragment hits were discovered by high concentration biochemical screening, followed by a round of virtual screening to identify additional ligand efficient fragments. These were developed into potent and ligand efficient lead compounds using structure guided fragment growing and merging strategies. This led to a potent, selective, and cell permeable PI3γ kinase inhibitor with good metabolic stability that was useful as a preclinical tool compound.
Assuntos
Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Ring-closing metathesis was used to construct the strained 11-membered ring of obtusallenes II (and IV). Bromonium ion induced transannular oxonium ion formation-fragmentation gave the macrocyclic carbon skeleton of obtusallene VII with a bromine atom at C-13, in line with a previously published hypothesis. An additional brominated [5.5.1]bicyclotridecane adduct that must arise from a bromonium ion induced transannular oxonium ion formation-fragmentation could also be isolated, suggesting that this adduct represents the core of an as yet undiscovered natural product. An authentic sample of obtusallene V was studied by NMR spectroscopy, and the position of the halogens at C-7 and C-13 was reassigned on the basis of a (13)C NMR chlorine induced isotopic shift. This revised structure was subsequently confirmed by X-ray crystallography. These findings allow us to confidently conclude that the structures of obtusallenes VII and VI should also be reassigned.
Assuntos
Bromo/química , Éteres Cíclicos/química , Oxigênio/química , Ciclização , Éteres Cíclicos/síntese química , Íons/química , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
[reaction: see text] Sharpless asymmetric dihydroxylation was regioselective for the trans olefin in an E vs Z vs terminal triene substrate. To test a biosynthetic hypothesis, the resulting diol underwent diastereoselective bromoetherification to provide the des-chloro core of marine natural products obtusallenes II and IV. Alternatively, anionic chloride ring-opening of a Z-beta,gamma-unsaturated epoxide gave separable regioisomeric halohydrins. Bromoetherification gave the fully elaborated core of obtusallenes II and IV with all of the relative stereochemistry correctly set.
Assuntos
Produtos Biológicos/química , Furanos/síntese química , Laurencia/química , Biologia Marinha , Bromo/química , Compostos de Epóxi/química , Éteres/química , Hidroxilação , Modelos Químicos , EstereoisomerismoRESUMO
A convergent total synthesis of phorboxazole A (1a), from the C(3-19), C(20-27) and C(33-46) fragments 5, 4 and 91, respectively, concentrating on stereocontrolled formation of the bonds at C(2-3), C(19-20) and C(27-28), is described. Although a coupling reaction between a macrolide ketone and the side chain substituted sulfone, at C(27-28) was not successful, a Wadsworth-Emmons olefination involving the oxane methyl ketone 4 and an oxazole produced the oxane 90 which was next coupled to 91 leading to the C(20-46) unit 100. A further coupling of 100 to 71c at C(19-20) then led to 105, ultimately, and the synthesis was completed by a macrocyclisation reaction from 105, at the C(2-3) alkene bond, followed by deprotection of 106.