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Introduction: Transient receptor potential vanilloid 4 (TRPV4) is an ion channel that is widely expressed and is activated by numerous chemical, osmotic and mechanical stimuli. By modulating Ca2+ entry, TRPV4 regulates cellular signaling associated with a variety of (patho)physiological processes and is a target of interest for treatment of human diseases including heart failure, respiratory diseases, gastrointestinal disorders, dermatological conditions, pain and cancer, among others.Areas covered: This article reviews small molecule TRPV4 antagonists and new therapeutic use claims disclosed in the patent literature from 2015 to 2020, including applications covering the first potent and selective TRPV4 clinical candidate and other advanced chemotypes.Expert opinion: TRPV4 has proven to be a tractable target and significant progress in discovery of TRPV4 antagonists has been realized in recent years. Several unique chemical templates with drug-like properties inhibit the channel and show efficacy in models that suggest their potential for treatment of a variety of diseases. While compelling clinical efficacy has not yet been seen in the limited early studies conducted with GSK2798745, evaluation of TRPV4 antagonists in larger trials across several indications is warranted given the availability of high-quality candidates and the promise of therapeutic benefit based on pre-clinical evidence.
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Bencimidazoles/farmacología , Desarrollo de Medicamentos , Compuestos de Espiro/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Descubrimiento de Drogas , Humanos , Patentes como Asunto , Canales Catiónicos TRPV/metabolismoRESUMEN
TRPV4 is a ubiquitously expressed, non-selective cation channel activated by a range of stimuli including hypotonicity, temperature, pH, stretch and endogenous ligands. Agents that modulate TRPV4 are sought as potential therapeutics for the treatment of many diseases including osteoarthritis, respiratory illnesses, gastrointestinal disorders, pain and congestive heart failure. In recent years, significant advances in TRPV4 drug discovery have been realized as at least seven novel TRPV4 agonist or antagonist templates were reported and the first selective TRPV4 antagonist was evaluated in early clinical trials.
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Productos Biológicos/farmacología , Forboles/farmacología , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/antagonistas & inhibidores , Productos Biológicos/química , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Estructura Molecular , Forboles/químicaRESUMEN
GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.
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Pirrolidinas/química , Sulfonamidas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Pirrolidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
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Edema Pulmonar/tratamiento farmacológico , Pirrolidinas/farmacología , Sulfonamidas/farmacología , Sulfonas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/química , Sulfonas/farmacocinéticaRESUMEN
A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure-activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.
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Diseño de Fármacos , Pirrolidinas/química , Sulfonamidas/química , Sulfonamidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Ratas , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinéticaRESUMEN
Herein, we describe the development of a functionally selective liver X receptor ß (LXRß) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-ß peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteínas E/líquido cefalorraquídeo , Benzamidas/química , Benzamidas/farmacología , Receptores Nucleares Huérfanos/agonistas , Piperidinas/química , Piperidinas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Células Hep G2 , Humanos , Lípidos/análisis , Hígado/efectos de los fármacos , Hígado/metabolismo , Receptores X del Hígado , Locomoción/efectos de los fármacos , Macaca mulatta , Células de Riñón Canino Madin Darby , Ratones , Ratones TransgénicosRESUMEN
We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
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Dolor Crónico/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Receptor trkA/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Humanos , Indoles/química , Indoles/farmacocinética , Ligandos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratas , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacocinética , Urea/análogos & derivados , Urea/química , Urea/farmacocinéticaRESUMEN
Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity.
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Oxazolidinonas/química , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológico , Regulación Alostérica , Animales , Antipsicóticos , Ketamina/toxicidad , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Ratas , Receptores de Glutamato Metabotrópico/agonistas , Relación Estructura-ActividadRESUMEN
Novel oxazolobenzimidazoles are described as potent and selective positive allosteric modulators of the metabotropic glutamate receptor 2. The discovery of this class and optimization of its physical and pharmacokinetic properties led to the identification of potent and orally bioavailable compounds (20 and 21) as advanced leads. Compound 20 (TBPCOB) was shown to have robust activity in a PCP-induced hyperlocomotion model in rat, an assay responsive to clinical antipsychotic treatments for schizophrenia.
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The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM).
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Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/efectos de los fármacos , Quinolonas/farmacología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cristalografía por Rayos X , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Quinolonas/química , Relación Estructura-ActividadRESUMEN
The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC(50)=0.30nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.