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1.
J Med Chem ; 66(12): 8130-8139, 2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37294287

RESUMEN

Pulmonary arterial hypertension (PAH) is a devastating rare disease, which despite currently available treatments, still represents a high unmet medical need. Specific E3 ubiquitin protein ligase 1 (SMURF1) is a HECT E3 ligase that ubiquitinates key signaling molecules from the TGFß/BMP pathways, which are of great relevance in the pathophysiology of PAH. Herein, the design and synthesis of novel potent small-molecule SMURF1 ligase inhibitors are described. Lead molecule 38 has demonstrated good oral pharmacokinetics in rats and significant efficacy in a rodent model of pulmonary hypertension.


Asunto(s)
Hipertensión Arterial Pulmonar , Ubiquitina-Proteína Ligasas , Ratas , Animales , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/metabolismo , Ubiquitinación , Pulmón/metabolismo
2.
Bioorg Med Chem Lett ; 20(17): 5161-4, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20685119

RESUMEN

A series of novel benzimidazole derivatives has been designed via a scaffold morphing approach based on known calcilytics chemotypes. Subsequent lead optimisation led to the discovery of penta-substituted benzimidazoles that exhibit attractive in vitro and in vivo calcium-sensing receptor (CaSR) inhibitory profiles. In addition, synthesis and structure-activity relationship data are provided.


Asunto(s)
Bencimidazoles/farmacología , Receptores Sensibles al Calcio/antagonistas & inhibidores , Bencimidazoles/química , Bencimidazoles/farmacocinética , Modelos Moleculares , Relación Estructura-Actividad
3.
J Med Chem ; 59(16): 7544-60, 2016 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-27502541

RESUMEN

Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.


Asunto(s)
Descubrimiento de Drogas , Imidazoles/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Quinolinas/farmacología , Animales , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas/metabolismo , Quinolinas/síntesis química , Quinolinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
4.
J Med Chem ; 53(5): 2250-63, 2010 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-20158186

RESUMEN

Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency could be improved >1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based on molecular modeling and confirmed by testing with mutated receptors. While the compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within minutes which reverted to baseline in about 1-2 h in both species.


Asunto(s)
Conservadores de la Densidad Ósea/síntesis química , Hormona Paratiroidea/metabolismo , Quinazolinonas/síntesis química , Receptores Sensibles al Calcio/metabolismo , Administración Oral , Animales , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/farmacocinética , Perros , Concentración 50 Inhibidora , Masculino , Quinazolinonas/administración & dosificación , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratas , Ratas Wistar , Receptores Sensibles al Calcio/antagonistas & inhibidores , Receptores Sensibles al Calcio/genética , Relación Estructura-Actividad
5.
J Biol Chem ; 282(32): 23231-9, 2007 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-17556356

RESUMEN

Inverse agonists of the constitutively active human estrogen-related receptor alpha (ERRalpha, NR3B1) are of potential interest for several disease indications (e.g. breast cancer, metabolic diseases, or osteoporosis). ERRalpha is constitutively active, because its ligand binding pocket (LBP) is practically filled with side chains (in particular with Phe(328), which is replaced by Ala in ERRbeta and ERRgamma). We present here the crystal structure of the ligand binding domain of ERRalpha (containing the mutation C325S) in complex with the inverse agonist cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine (compound 1a), to a resolution of 2.3A(.) The structure reveals the dramatic multiple conformational changes in the LBP, which create the necessary space for the ligand. As a consequence of the new side chain conformation of Phe(328) (on helix H3), Phe(510)(H12) has to move away, and thus the activation helix H12 is displaced from its agonist position. This is a novel mechanism of H12 inactivation, different from ERRgamma, estrogen receptor (ER) alpha, and ERbeta. H12 binds (with a surprising binding mode) in the coactivator groove of its ligand binding domain, at a similar place as a coactivator peptide. This is in contrast to ERRgamma but resembles the situation for ERalpha (raloxifene or 4-hydroxytamoxifen complexes). Our results explain the novel molecular mechanism of an inverse agonist for ERRalpha and provide the basis for rational drug design to obtain isotype-specific inverse agonists of this potential new drug target. Despite a practically filled LBP, the finding that a suitable ligand can induce an opening of the cavity also has broad implications for other orphan nuclear hormone receptors (e.g. the NGFI-B subfamily).


Asunto(s)
Receptores de Estrógenos/química , Cristalografía por Rayos X , Diseño de Fármacos , Receptor alfa de Estrógeno/química , Humanos , Cinética , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Nitrógeno/química , Unión Proteica , Conformación Proteica , Estructura Terciaria de Proteína , Receptor Relacionado con Estrógeno ERRalfa
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