RESUMEN
Fast and accurate assessment of small-molecule dihedral energetics is crucial for molecular design and optimization in medicinal chemistry. Yet, accurate prediction of torsion energy profiles remains challenging as the current molecular mechanics (MM) methods are limited by insufficient coverage of drug-like chemical space and accurate quantum mechanical (QM) methods are too expensive. To address this limitation, we introduce TorsionNet, a deep neural network (DNN) model specifically developed to predict small-molecule torsion energy profiles with QM-level accuracy. We applied active learning to identify nearly 50k fragments (with elements H, C, N, O, F, S, and Cl) that maximized the coverage of our corporate compound library and leveraged massively parallel cloud computing resources for density functional theory (DFT) torsion scans of these fragments, generating a training data set of 1.2 million DFT energies. After training TorsionNet on this data set, we obtain a model that can rapidly predict the torsion energy profile of typical drug-like fragments with DFT-level accuracy. Importantly, our method also provides an uncertainty estimate for the predicted profiles without any additional calculations. In this report, we show that TorsionNet can accurately identify the preferred dihedral geometries observed in crystal structures. Our TorsionNet-based analysis of a diverse set of protein-ligand complexes with measured binding affinity shows a strong association between high ligand strain and low potency. We also present practical applications of TorsionNet that demonstrate how consideration of DNN-based strain energy leads to substantial improvement in existing lead discovery and design workflows. TorsionNet500, a benchmark data set comprising 500 chemically diverse fragments with DFT torsion profiles (12k MM- and DFT-optimized geometries and energies), has been created and is made publicly available.
Asunto(s)
Redes Neurales de la Computación , Teoría Cuántica , Ligandos , Simulación de Dinámica Molecular , TermodinámicaRESUMEN
The energetics of rotation around single bonds (torsions) is a key determinant of the three-dimensional shape that druglike molecules adopt in solution, the solid state, and in different biological environments, which in turn defines their unique physical and pharmacological properties. Therefore, accurate characterization of torsion angle preference and energetics is essential for the success of computational drug discovery and design. Here, we analyze torsional strain in crystal structures of druglike molecules in Cambridge structure database (CSD) and bioactive ligand conformations in protein data bank (PDB), expressing the total strain energy as a sum of strain energy from constituent rotatable bonds. We utilized cloud computing to generate torsion scan profiles of a very large collection of chemically diverse neutral fragments at DFT(B3LYP)/6-31G*//6-31G** or DFT(B3LYP)/6-31+G*//6-31+G** (for sulfur-containing molecule). With the data generated from these ab initio calculations, we performed rigorous analysis of strain due to deviation of observed torsion angles relative to their ideal gas-phase geometries. Contrary to the previous studies based on molecular mechanics, we find that in the crystalline state, molecules generally adopt low-strain conformations, with median per-torsion strain energy in CSD and PDB under one-tenth and one-third of a kcal/mol, respectively. However, for a small fraction (<5%) of motifs, external effects such as steric hindrance and hydrogen bonds result in strain penalty exceeding 2.5 kcal/mol. We find that due to poor quality of PDB structures in general, bioactive structures tend to have higher torsional strain compared to small-molecule crystal conformations. However, in the absence of structural fitting artifacts in PDB structures, protein-induced strain in bioactive conformations is quantitatively similar to those due to the packing forces in small-molecule crystal structures. This analysis allows us to establish strain energy thresholds to help identify biologically relevant conformers in a given ensemble. The work presented here is the most comprehensive study to date that demonstrates the utility and feasibility of gas-phase quantum mechanics (QM) calculations to study conformational preference and energetics of drug-size molecules. Potential applications of this study in computational lead discovery and structure-based design are discussed.
Asunto(s)
Descubrimiento de Drogas , Proteínas/química , Bases de Datos de Compuestos Químicos , Enlace de Hidrógeno , Ligandos , Conformación Molecular , Estructura Molecular , Rotación , Bibliotecas de Moléculas PequeñasRESUMEN
ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell-mediated inflammatory diseases. In the present study we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared with the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by steady-state enzyme kinetics. The activity of the isolated kinase domain and auto-activation of the full-length enzyme were inhibited with similar potency. However, inhibition of the activated full-length enzyme was weaker, presumably because the allosteric site is altered when ITK becomes activated. An optimized lead showed exquisite kinome selectivity and is efficacious in human whole blood and proximal cell-based assays.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/farmacología , Regulación Alostérica , Sitio Alostérico , Cristalización , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Conformación Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Resonancia por Plasmón de SuperficieRESUMEN
The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.
Asunto(s)
Receptores CCR6 , Receptores CCR6/metabolismo , Receptores CCR6/química , Humanos , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico , Unión Proteica , Sitios de Unión , Modelos Moleculares , Cristalografía por Rayos XRESUMEN
Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.
RESUMEN
High throughput microsomal stability assays have been widely implemented in drug discovery and many companies have accumulated experimental measurements for thousands of compounds. Such datasets have been used to develop in silico models to predict metabolic stability and guide the selection of promising candidates for synthesis. This approach has proven most effective when selecting compounds from proposed virtual libraries prior to synthesis. However, these models are not easily interpretable at the structural level, and thus provide little insight to guide traditional synthetic efforts. We have developed global classification models of rat, mouse and human liver microsomal stability using in-house data. These models were built with FCFP_6 fingerprints using a Naïve Bayesian classifier within Pipeline Pilot. The test sets were correctly classified as stable or unstable with satisfying accuracies of 78, 77 and 75% for rat, human and mouse models, respectively. The prediction confidence was assigned using the Bayesian score to assess the applicability of the models. Using the resulting models, we developed a novel data mining strategy to identify structural features associated with good and bad microsomal stability. We also used this approach to identify structural features which are good for one species but bad for another. With these findings, the structure-metabolism relationships are likely to be understood faster and earlier in drug discovery.
Asunto(s)
Microsomas Hepáticos/metabolismo , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Relación Estructura-Actividad Cuantitativa , Animales , Descubrimiento de Drogas , Monitoreo del Ambiente , Femenino , Humanos , Masculino , Ratones , Estructura Molecular , RatasRESUMEN
Pyrrole[2,3-d]azepines have been identified as potent agonists of the farnesoid X receptor (FXR). Based on the planar X-ray crystal structure of WAY-362450 1 in the ligand binding domain and molecular modeling studies, non-planar reduced compounds were designed which led to agonists that exhibit high aqueous solubility and retain moderate in vitro potency.
Asunto(s)
Azepinas/farmacología , Pirroles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Azepinas/química , Humanos , Modelos Moleculares , Unión Proteica , Pirroles/química , Receptores Citoplasmáticos y Nucleares/química , Relación Estructura-ActividadRESUMEN
A series of novel 7-(5'-cyanopyrrol-2-yl) substituted benzo[1,4]oxazepin-2-ones were prepared and tested for their progesterone receptor (PR) agonist or antagonist activity in the alkaline phosphatase assay using the human T47D breast carcinoma cell line. Both PR agonists and antagonists were achieved with an appropriate choice of 5-substitution. Several analogs were potent PR agonists (e.g., 12 and 13) or PR antagonists (e.g., 18) with good selectivity over other steroid receptors.
Asunto(s)
Oxazepinas/síntesis química , Oxazepinas/farmacología , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inhibidores , Técnicas Químicas Combinatorias , Humanos , Estructura Molecular , Oxazepinas/química , Receptores de Progesterona/metabolismo , Relación Estructura-ActividadRESUMEN
Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC(50) of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.
Asunto(s)
Benzazepinas/síntesis química , Benzazepinas/farmacología , Oxazepinas/síntesis química , Oxazepinas/farmacología , Receptores de Progesterona/antagonistas & inhibidores , Fosfatasa Alcalina/antagonistas & inhibidores , Fosfatasa Alcalina/metabolismo , Animales , Benzazepinas/química , Sitios de Unión , Células COS , Chlorocebus aethiops , Femenino , Hidroxilación , Modelos Moleculares , Estructura Molecular , Oxazepinas/química , Receptores de Progesterona/metabolismo , Relación Estructura-ActividadRESUMEN
Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
Asunto(s)
Cianamida/química , Cianamida/farmacología , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Cianamida/farmacocinética , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 3/química , Masculino , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Distribución TisularRESUMEN
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Ciclobutanos/farmacología , Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Animales , Artritis Experimental/tratamiento farmacológico , Ciclobutanos/química , Ciclobutanos/farmacocinética , Ciclobutanos/uso terapéutico , Perros , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 1/química , Janus Quinasa 2/antagonistas & inhibidores , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Pirroles/química , Pirroles/farmacocinética , Pirroles/uso terapéutico , Ratas , Especificidad por Sustrato , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Distribución TisularRESUMEN
Bruton tyrosine kinase (BTK) is a key enzyme in B-cell development whose improper regulation causes severe immunodeficiency diseases. Design of selective BTK therapeutics would benefit from improved, in-silico structural modeling of the kinase's solution ensemble. However, this remains challenging due to the immense computational cost of sampling events on biological timescales. In this work, we combine multi-millisecond molecular dynamics (MD) simulations with Markov state models (MSMs) to report on the thermodynamics, kinetics, and accessible states of BTK's kinase domain. Our conformational landscape links the active state to several inactive states, connected via a structurally diverse intermediate. Our calculations predict a kinome-wide conformational plasticity, and indicate the presence of several new potentially druggable BTK states. We further find that the population of these states and the kinetics of their inter-conversion are modulated by protonation of an aspartate residue, establishing the power of MD & MSMs in predicting effects of chemical perturbations.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/química , Linfocitos B/enzimología , Simulación de Dinámica Molecular , Conformación Proteica , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Linfocitos B/química , Simulación por Computador , Humanos , Cinética , Cadenas de Markov , TermodinámicaRESUMEN
In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.
Asunto(s)
Anabolizantes/química , Andrógenos/química , Nitrilos/química , Pirroles/química , Receptores Androgénicos/metabolismo , Anabolizantes/síntesis química , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Andrógenos/síntesis química , Andrógenos/farmacocinética , Andrógenos/farmacología , Animales , Cristalografía por Rayos X , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Nitrilos/síntesis química , Nitrilos/farmacología , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos , Próstata/efectos de los fármacos , Próstata/fisiología , Pirroles/síntesis química , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Vesículas Seminales/efectos de los fármacos , Vesículas Seminales/fisiología , Relación Estructura-ActividadRESUMEN
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of 11 (PF-06651600), a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor 11 led to its evaluation in several human clinical studies.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Pirroles/química , Transducción de Señal/efectos de los fármacos , Administración Oral , Diseño de Fármacos , Humanos , Janus Quinasa 3/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Pirroles/administración & dosificación , Pirroles/farmacologíaRESUMEN
PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Importantly, by sparing JAK1 function, PF-06651600 selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling such as the IL-10 suppressive functions following LPS treatment in macrophages and the suppression of TNFα and IL-1ß production in IL-27-primed macrophages. Thus, JAK3-selective inhibition differentiates from pan-JAK or JAK1 inhibition in various immune cellular responses, which could potentially translate to advantageous clinical outcomes in inflammatory and autoimmune diseases.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Animales , Artritis Experimental/inmunología , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Interleucina-10/inmunología , Interleucina-1beta/inmunología , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 3/metabolismo , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Células TH1/citología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/citología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.
Asunto(s)
Benzoxazinas/síntesis química , Oxazinas/síntesis química , Pirroles/síntesis química , Receptores de Progesterona/agonistas , Tionas/síntesis química , Fosfatasa Alcalina/metabolismo , Animales , Área Bajo la Curva , Benzoxazinas/química , Benzoxazinas/farmacología , Unión Competitiva , Línea Celular Tumoral , Anticonceptivos Femeninos/síntesis química , Anticonceptivos Femeninos/química , Anticonceptivos Femeninos/farmacología , Decidua/efectos de los fármacos , Decidua/metabolismo , Femenino , Semivida , Humanos , Técnicas In Vitro , Ligandos , Estructura Molecular , Oxazinas/química , Oxazinas/farmacología , Estructura Terciaria de Proteína , Pirroles/química , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Progesterona/antagonistas & inhibidores , Receptores de Progesterona/química , Relación Estructura-Actividad , Tionas/química , Tionas/farmacologíaRESUMEN
Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addition to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochemical and pharmacokinetic properties. Analysis of anisole and fluoroanisole matched molecular pairs in the Pfizer corporate database reveals interesting trends: 1) PhOCF3 increases log D by ~1 log unit over PhOCH3 compounds; 2) PhOCF3 shows lower passive permeability despite its higher lipophilicity; and 3) PhOCF3 does not appreciably improve metabolic stability over PhOCH3 . Emerging from the investigation, difluoroanisole (PhOCF2 H) strikes a better balance of properties with noticeable advantages of log D and transcellular permeability over PhOCF3 . Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, our analysis suggests PhOCF2 H may be a more attractive alternative, and greater exploitation of this motif is recommended.
Asunto(s)
Anisoles/química , Diseño de Fármacos , Flúor/química , Animales , Anisoles/metabolismo , Anisoles/farmacocinética , Línea Celular , Perros , Flúor/metabolismo , Flúor/farmacocinética , Halogenación , Humanos , Ligandos , Microsomas Hepáticos/metabolismo , PermeabilidadRESUMEN
A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.
Asunto(s)
Osteogénesis/efectos de los fármacos , Piperidinas/farmacología , Pirimidinas/farmacología , Proteínas Wnt/agonistas , beta Catenina/agonistas , Animales , Dominio Catalítico , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/química , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , Modelos Moleculares , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Ratas , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
We have recently discovered 5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (14) as a potent, selective, and orally active non-steroidal progesterone receptor (PR) agonist. Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0.1-0.5nM) in the T47D alkaline phosphatase assay, similar to that of the steroidal PR agonist medroxyprogesterone acetate (MPA). In contrast to MPA, 14 was highly selective (>500-fold) for the PR over both glucocorticoid and androgen receptors. In the rat uterine decidualization and complement component C3 models, 14 had oral ED(50) values of 0.02 and 0.003mg/kg, respectively, and was from 6- to 20-fold more potent than MPA. In the monkey ovulation inhibition model, compound 14 was also highly efficacious and potent with an oral ED(100) of 0.03mg/kg.