RESUMEN
Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues.
RESUMEN
A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.
RESUMEN
Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.
Asunto(s)
Inhibidores de las Cinasas Janus , Vitíligo , Ratones , Animales , Humanos , ARN Interferente Pequeño/genética , Linfocitos T CD8-positivos/metabolismo , Autoinmunidad/genética , Vitíligo/tratamiento farmacológico , Vitíligo/genética , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , ARN BicatenarioRESUMEN
In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.
RESUMEN
Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.
RESUMEN
A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
Asunto(s)
Antineoplásicos/farmacología , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Quinina/análogos & derivados , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/patología , Modelos Moleculares , Estructura Molecular , Quinina/síntesis química , Quinina/química , Quinina/farmacología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Solubilidad , Relación Estructura-ActividadRESUMEN
Retinoids have a dominant role in topical acne therapy and to date, only RARß and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.
Asunto(s)
Acné Vulgar/tratamiento farmacológico , Diseño de Fármacos , Receptores de Ácido Retinoico/agonistas , Retinoides/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Retinoides/síntesis química , Retinoides/química , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.
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Acné Vulgar/tratamiento farmacológico , Caspasa 1/metabolismo , Inhibidores de Caspasas/administración & dosificación , Inhibidores de Caspasas/farmacología , Diseño de Fármacos , Acné Vulgar/enzimología , Administración Tópica , Animales , Caspasa 1/química , Inhibidores de Caspasas/farmacocinética , Inhibidores de Caspasas/uso terapéutico , Línea Celular , Humanos , Ratones , Modelos Moleculares , Conformación Proteica , Solventes/química , Distribución TisularRESUMEN
Phototoxicity occurs when UV irradiation causes otherwise benign compounds to become irritant, sensitizers, or even genotoxic. This toxicity is particularly a concern after topical application and in dermatological programs where skin irritation can be incompatible with the desired therapeutic outcome. This brief article establishes that the intrinsic property forecast index (iPFI) can be used to evaluate the probability of a compound being phototoxic and gives medicinal chemists a practical tool to handle this liability.
Asunto(s)
Algoritmos , Química Farmacéutica/métodos , Dermatitis Fototóxica , Heurística , Células 3T3 , Animales , Electrones , Predicción , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Ratones , Fármacos Fotosensibilizantes , Relación Estructura-Actividad , Rayos UltravioletaRESUMEN
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.
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Iminas/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Sulfonamidas/farmacología , Sulfóxidos/farmacología , Animales , Agonismo Inverso de Drogas , Femenino , Humanos , Iminas/síntesis química , Iminas/química , Ligandos , Ratones Endogámicos BALB C , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfóxidos/síntesis química , Sulfóxidos/químicaRESUMEN
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with inâ vivo activity in an IL-23-induced mouse skin inflammation model.
Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Psoriasis/tratamiento farmacológico , Sulfonamidas/química , Administración Tópica , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Humanos , Concentración 50 Inhibidora , Interleucina-17/metabolismo , Interleucina-23/farmacología , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Psoriasis/patología , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Células Th17/citología , Células Th17/efectos de los fármacos , Células Th17/metabolismoRESUMEN
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.
Asunto(s)
Proteína ADAM17/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Proteína ADAM17/metabolismo , Administración Tópica , Animales , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Ácidos Hidroxámicos/química , Ratones , Ratones Pelados , Microsomas Hepáticos/metabolismo , Oxazolona/toxicidad , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/prevención & control , Enfermedades de la Piel/veterinaria , Solubilidad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
Asunto(s)
Proteína ADAM17/antagonistas & inhibidores , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/química , Proteína ADAM17/metabolismo , Administración Tópica , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/enzimologíaRESUMEN
Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.