RESUMEN
The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.
Asunto(s)
Éteres/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Tretinoina/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Éteres/síntesis química , Éteres/química , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Células Th17 , Tretinoina/síntesis química , Tretinoina/químicaRESUMEN
In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.
Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Pirrolidinas/farmacología , Sulfonas/farmacología , Animales , Cristalografía por Rayos X , Descubrimiento de Drogas , Agonismo Inverso de Drogas , Estabilidad de Medicamentos , Células Hep G2 , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/metabolismoRESUMEN
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Animales , Presión Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Quinasas Asociadas a rho/metabolismoRESUMEN
A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.
Asunto(s)
Diseño de Fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Pirrolidinas/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Agonismo Inverso de Drogas , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Receptor X de Pregnano/agonistas , Receptor X de Pregnano/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Relación Estructura-ActividadRESUMEN
Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.
Asunto(s)
Compuestos de Bencilo/farmacología , Compuestos Heterocíclicos/farmacología , Receptores de Ácido Retinoico/agonistas , Animales , Compuestos de Bencilo/química , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos/química , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.
Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacología , Sulfonas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Agonismo Inverso de Drogas , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Pirrolidinas/administración & dosificación , Pirrolidinas/química , Relación Estructura-Actividad , Sulfonas/administración & dosificación , Sulfonas/químicaRESUMEN
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacología , Diseño de Fármacos , Propanoles/farmacología , Receptores de Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacología , Animales , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Receptores X del Hígado/agonistas , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Receptor X de Pregnano , Propanoles/síntesis química , Propanoles/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Receptor de Ácido Retinoico gammaRESUMEN
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.
Asunto(s)
Diseño de Fármacos , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Niacinamida/química , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Janus Quinasa 3/química , Janus Quinasa 3/metabolismo , Conformación Molecular , Simulación de Dinámica Molecular , Niacinamida/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.
Asunto(s)
Aminas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Aminas/metabolismo , Aminas/uso terapéutico , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Sitios de Unión , Fosfatidilinositol 3-Quinasa Clase I , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridazinas/química , Pirroles/química , Animales , Sitios de Unión , Dominio Catalítico , Línea Celular , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Inflamación/prevención & control , Concentración 50 Inhibidora , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridazinas/síntesis química , Piridazinas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , TYK2 Quinasa/antagonistas & inhibidores , TYK2 Quinasa/metabolismoRESUMEN
Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.
Asunto(s)
Aminas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapéutico , Animales , Artritis/tratamiento farmacológico , Artritis/metabolismo , Artritis/patología , Sitios de Unión , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
Asunto(s)
Amidas/química , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Amidas/metabolismo , Amidas/farmacología , Sitios de Unión , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Janus Quinasa 3/antagonistas & inhibidores , Janus Quinasa 3/metabolismo , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.
Asunto(s)
Descubrimiento de Drogas , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/química , Pirroles/química , Administración Oral , Animales , Ensayo de Inmunoadsorción Enzimática , Humanos , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Conformación Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Distribución TisularRESUMEN
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Simulación de Dinámica Molecular , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.
Asunto(s)
Indoles/antagonistas & inhibidores , Indoles/química , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/química , Pirazoles/antagonistas & inhibidores , Pirazoles/química , Secuencia de Aminoácidos , Dominio Catalítico/efectos de los fármacos , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Indoles/metabolismo , Datos de Secuencia Molecular , Unión Proteica/efectos de los fármacos , Proteína-Arginina N-Metiltransferasas/metabolismo , Pirazoles/metabolismoRESUMEN
The X-ray crystal structure of a human cardiac muscle troponin C/troponin I chimera has been determined in two different crystal forms and shows a conformation of the complex that differs from that previously observed by NMR. The chimera consists of the N-terminal domain of troponin C (cTnC; residues 1-80) fused to the switch region of troponin I (cTnI; residues 138-162). In both crystal forms, the cTnI residues form a six-turn α-helix that lays across the hydrophobic groove of an adjacent cTnC molecule in the crystal structure. In contrast to previous models, the cTnI helix runs in a parallel direction relative to the cTnC groove and completely blocks the calcium desensitizer binding site of the cTnC-cTnI interface.
Asunto(s)
Troponina C , Troponina I , Calcio/química , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Miocardio/química , Unión Proteica , Proteínas Recombinantes de Fusión/química , Troponina C/análisis , Troponina C/química , Troponina I/análisis , Troponina I/químicaRESUMEN
The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2',3'-cGAMP (1) (an endogenous STING activator ligand) and other closely related cyclic dinucleotides (CDNs). While these efforts have successfully identified novel CDNs that have progressed into the clinic, their utility is currently limited to patients with solid tumors that STING agonists can be delivered to intratumorally. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model.
Asunto(s)
Proteínas de la Membrana/agonistas , Animales , Cristalografía por Rayos X , AMP Cíclico/química , AMP Cíclico/farmacología , GMP Cíclico/química , GMP Cíclico/farmacología , Femenino , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunoterapia/métodos , Proteínas de la Membrana/química , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Neoplasias/inmunología , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas PequeñasRESUMEN
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Asunto(s)
Antiinflamatorios/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Triazinas/química , Administración Oral , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Artritis/tratamiento farmacológico , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Ratones , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Triazinas/farmacología , Triazinas/uso terapéuticoRESUMEN
SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.