RESUMEN
The status of industrial Medicinal Chemistry was discussed with European Medicinal Chemistry Leaders from large to mid-sized pharma and CRO companies as well as biotechs. The chemical modality space has expanded recently from small molecules to address new challenging targets. Besides the classical SAR/SPR optimization of drug molecules also their 'greenness' has increasing importance. The entire pharma discovery ecosystem has developed significantly. Beyond pharma and academia new key players such as Biotech and integrated CROs as well as Digital companies have appeared and are now to a large extend fueled by VC money. Digitalization is happening everywhere but surprisingly did not change speed and success rates of projects so far. Future Medicinal Chemists will still have to be excellent synthetic chemists but in addition they must be knowledgeable in new computational areas such as data sciences. Their ability to collaborate and to work in teams is key.
Asunto(s)
Química Farmacéutica , Industria Farmacéutica , Ecosistema , Europa (Continente)RESUMEN
Fibroblast growth factor receptors (FGFRs) and associated ligands (FGFs) are a family of well-validated targets for therapeutic interventions notably in cancer diseases in relation to their prominent roles in cell growth, survival, differentiation and angiogenesis. This patent review encompasses all different approaches (modulators of FGF or FGFR expression, anti-FGF antibodies, anti-FGFR antibodies, FGF traps, tyrosine-kinase (TK) inhibitors, allosteric modulators) used to block completely or partially the activities of the FGF-FGFR complexes resulting in clinical drug candidates or tool agents. Comparative analysis of biochemical, pharmacological or clinical data will be discussed for each class of molecules together with some perspectives.
Asunto(s)
Factores de Crecimiento de Fibroblastos , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento de Fibroblastos , Animales , Anticuerpos/uso terapéutico , Antineoplásicos/uso terapéutico , Aptámeros de Nucleótidos/uso terapéutico , Factores de Crecimiento de Fibroblastos/inmunología , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Patentes como Asunto , Péptidos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/inmunología , Receptores de Factores de Crecimiento de Fibroblastos/metabolismoRESUMEN
Despite the importance of the microbiota in human physiology, the molecular bases that govern the interactions between these commensal bacteria and their host remain poorly understood. We recently reported that sulfatases play a key role in the adaptation of a major human commensal bacterium, Bacteroides thetaiotaomicron, to its host (Benjdia, A., Martens, E. C., Gordon, J. I., and Berteau, O. (2011) J. Biol. Chem. 286, 25973-25982). We hypothesized that sulfatases are instrumental for this bacterium, and related Bacteroides species, to metabolize highly sulfated glycans (i.e. mucins and glycosaminoglycans (GAGs)) and to colonize the intestinal mucosal layer. Based on our previous study, we investigated 10 sulfatase genes induced in the presence of host glycans. Biochemical characterization of these potential sulfatases allowed the identification of GAG-specific sulfatases selective for the type of saccharide residue and the attachment position of the sulfate group. Although some GAG-specific bacterial sulfatase activities have been described in the literature, we report here for the first time the identity and the biochemical characterization of four GAG-specific sulfatases. Furthermore, contrary to the current paradigm, we discovered that B. thetaiotaomicron possesses an authentic GAG endosulfatase that is active at the polymer level. This type of sulfatase is the first one to be identified in a bacterium. Our study thus demonstrates that bacteria have evolved more sophisticated and diverse GAG sulfatases than anticipated and establishes how B. thetaiotaomicron, and other major human commensal bacteria, can metabolize and potentially tailor complex host glycans.
Asunto(s)
Bacteroides/enzimología , Glicosaminoglicanos/metabolismo , Sulfatasas/metabolismo , Simbiosis , Secuencia de Bases , Secuencia de Carbohidratos , Cartilla de ADN , Glicosaminoglicanos/química , Humanos , Espectroscopía de Resonancia Magnética , Datos de Secuencia MolecularRESUMEN
In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.
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Indoles/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2/farmacología , Piridazinas/farmacología , Receptores Purinérgicos P2Y12/metabolismo , Síndrome Coronario Agudo/prevención & control , Adenosina Difosfato/farmacología , Administración Oral , Animales , Unión Competitiva , Células CHO , Cricetinae , Cricetulus , Humanos , Indoles/síntesis química , Indoles/metabolismo , Inyecciones Intravenosas , Masculino , Modelos Químicos , Estructura Molecular , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/metabolismo , Antagonistas del Receptor Purinérgico P2/síntesis química , Antagonistas del Receptor Purinérgico P2/metabolismo , Piridazinas/síntesis química , Piridazinas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2Y12/genética , Trombosis/prevención & controlRESUMEN
Compound 15 (SAR107375), a novel potent dual thrombin and factor Xa inhibitor resulted from a rational optimization process. Starting from compound 14, with low factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and 0.39 µM, respectively), both activities were considerably improved, notably through the incorporation of a neutral chlorothiophene P1 fragment and tuning of P2 and P3-P4 fragments. Final optimization of metabolic stability with microsomes led to the identification of 15, which displays strong activity in vitro vs factor Xa and thrombin (with Ki's of 1 and 8 nM, respectively). In addition 15 presents good selectivity versus related serine proteases (roughly 300-fold), including trypsin (1000-fold), and is very active (0.39 µM) in the thrombin generation time (TGT) coagulation assay in human platelet rich plasma (PRP). Potent in vivo activity in a rat model of venous thrombosis following iv and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8 mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model, more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate 1a.
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Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Fibrinolíticos/síntesis química , Piperazinas/síntesis química , Sulfonamidas/síntesis química , Trombina/antagonistas & inhibidores , Animales , Anticoagulantes/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Fibrinolíticos/farmacología , Humanos , Piperazinas/farmacología , Piperazinas/uso terapéutico , Ratas , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
The fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling network plays an important role in cell growth, survival, differentiation, and angiogenesis. Deregulation of FGFR signaling can lead to cancer development. Here, we report an FGFR inhibitor, SSR128129E (SSR), that binds to the extracellular part of the receptor. SSR does not compete with FGF for binding to FGFR but inhibits FGF-induced signaling linked to FGFR internalization in an allosteric manner, as shown by crystallography studies, nuclear magnetic resonance, Fourier transform infrared spectroscopy, molecular dynamics simulations, free energy calculations, structure-activity relationship analysis, and FGFR mutagenesis. Overall, SSR is a small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR.
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Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Regulación Alostérica/efectos de los fármacos , Unión Competitiva , Procesos de Crecimiento Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Conformación Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Fibroblast growth factor (FGF) signaling regulates mammalian development and metabolism, and its dysregulation is implicated in many inherited and acquired diseases, including cancer. Heparan sulfate glycosaminoglycans (HSGAGs) are essential for FGF signaling as they promote FGF.FGF receptor (FGFR) binding and dimerization. Using novel organic synthesis protocols to prepare homogeneously sulfated heparin mimetics (HM), including hexasaccharide (HM(6)), octasaccharide (HM(8)), and decasaccharide (HM(10)), we tested the ability of these HM to support FGF1 and FGF2 signaling through FGFR4. Biological assays show that both HM(8) and HM(10) are significantly more potent than HM(6) in promoting FGF2-mediated FGFR4 signaling. In contrast, all three HM have comparable activity in promoting FGF1.FGFR4 signaling. To understand the molecular basis for these differential activities in FGF1/2.FGFR4 signaling, we used NMR spectroscopy, isothermal titration calorimetry, and size-exclusion chromatography to characterize binding interactions of FGF1/2 with the isolated Ig-domain 2 (D2) of FGFR4 in the presence of HM, and binary interactions of FGFs and D2 with HM. Our data confirm the existence of both a secondary FGF1.FGFR4 interaction site and a direct FGFR4.FGFR4 interaction site thus supporting the formation of the symmetric mode of FGF.FGFR dimerization in solution. Moreover, our results show that the observed higher activity of HM(8) relative to HM(6) in stimulating FGF2.FGFR4 signaling correlates with the higher affinity of HM(8) to bind and dimerize FGF2. Notably FGF2.HM(8) exhibits pronounced positive binding cooperativity. Based on our findings we propose a refined symmetric FGF.FGFR dimerization model, which incorporates the differential ability of HM to dimerize FGFs.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Heparina/análogos & derivados , Oligosacáridos/farmacología , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Animales , Sitios de Unión , Línea Celular , Humanos , Ratones , Complejos Multiproteicos/biosíntesis , Oligosacáridos/química , Unión Proteica , Multimerización de Proteína , Relación Estructura-ActividadRESUMEN
SSR182289A 1 is the result of a rational optimisation process leading to an orally active thrombin inhibitor. The structure incorporates an original 2-(acetylamino)-[1,1'-biphenyl]-3-sulfonyl N-terminal motif, a central l-Arg surrogate carrying a weakly basic 3-amino-pyridine, and an unusual 4-difluoropiperidine at the C-terminus. Its synthesis is convergent and palladium catalysis has been employed for the construction of the key C-C bonds: Suzuki coupling for the bis-aryl fragment and Sonogashira reaction for the delta- bond of the central amino-acid chain. The compound is a potent inhibitor of thrombin's activities in vitro and demonstrates potent oral anti-thrombotic potencies in three rat models of thrombosis. The observed in vitro potency could be rationalized through the examination of the interactions within the SSR182289A 1 - thrombin crystal structure. SSR182289A 1, has been therefore selected for further development.
Asunto(s)
Aminopiridinas/farmacología , Sulfonamidas/farmacología , Trombina/antagonistas & inhibidores , Administración Oral , Aminopiridinas/síntesis química , Animales , Azetidinas/farmacología , Bencilaminas , Coagulación Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Enlace de Hidrógeno , Masculino , Modelos Moleculares , Estructura Molecular , Agregación Plaquetaria/efectos de los fármacos , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Trombina/fisiología , Trombosis/tratamiento farmacológico , Trombosis/fisiopatología , Trombosis/prevención & controlRESUMEN
SSR182289A competitively inhibits human thrombin (K(i) = 0.031 +/- 0.002 microM) and shows good selectivity with respect to other human proteases, e.g., trypsin (K(i) = 54 +/- 2 microM), factor Xa (K(i) = 167 +/- 9 microM), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K(i) values >250 microM). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC100 thrombin time 96 +/- 7 nM) and inhibited tissue factor-induced thrombin generation (IC50 of 0.15 +/- 0.02 microM). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC50 value of 32 +/- 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 +/- 356%; ecarin clotting time (ECT), 1134 +/- 204%; and activated partial thromboplastin time (aPTT), 91 +/- 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 +/- 425%; ECT, 2017 +/- 341%; and aPTT, 113 +/- 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.