RESUMEN
In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.
RESUMEN
A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Benzofuranos/farmacología , Hidantoínas/farmacología , Osteoartritis/tratamiento farmacológico , Procolágeno N-Endopeptidasa/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Proteína ADAMTS4 , Proteína ADAMTS5 , Animales , Benzofuranos/química , Células Cultivadas , Cristalografía por Rayos X , Hidantoínas/química , Masculino , Meniscos Tibiales/efectos de los fármacos , Meniscos Tibiales/patología , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Modelos Anatómicos , Modelos Moleculares , Estructura Molecular , Osteoartritis/patología , Inhibidores de Proteasas/química , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Lesiones de Menisco TibialRESUMEN
We report the novel combination of a selective beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor (sibutramine) with potential for the treatment of obesity. The synthesis and characterization of 6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide (LY377604), a human ß3-adrenergic receptor agonist and ß1- and ß2-adrenergic receptor antagonist with no sympathomimetic activity at the ß1- and ß2-adrenergic receptors, is reported. Some in vivo data in both rats and humans is presented.
RESUMEN
The synthesis and biological evaluation of a series of benzimidazolone beta(3) adrenergic receptor agonists are described. A trend toward the reduction of rat atrial tachycardia upon increasing steric bulk at the 3-position of the benzimidazolone moiety was observed.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacología , Bencimidazoles/farmacología , Agonistas Adrenérgicos beta/química , Bencimidazoles/química , HumanosRESUMEN
To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.
Asunto(s)
Cinamatos/síntesis química , Modelos Moleculares , PPAR alfa/agonistas , Animales , Cinamatos/química , Cinamatos/farmacología , Diseño de Fármacos , Humanos , Ligandos , Ratones , Estructura Molecular , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Fenilpropionatos/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/síntesis química , Factores de Transcripción/agonistas , Animales , Unión Competitiva , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacología , Fenilpropionatos/química , Fenilpropionatos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Zucker , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-gamma agonist, which were presumably due to the concomitant PPAR-alpha agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovascular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.