RESUMEN
Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values <3 mg/kg.
Asunto(s)
Conducta Animal/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Canales Catiónicos TRPM/antagonistas & inhibidores , Tetrahidroisoquinolinas/farmacocinética , Animales , Dicroismo Circular , Frío , Perros , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Pirimidinonas/farmacología , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Estereoisomerismo , Canales Catiónicos TRPM/metabolismo , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacología , Distribución TisularRESUMEN
The transient receptor potential melastatin type 8 (TRPM8) is a nonselective cation channel primarily expressed in a subpopulation of sensory neurons that can be activated by a wide range of stimuli, including menthol, icilin, and cold temperatures (<25 °C). Antagonism of TRPM8 is currently under investigation as a new approach for the treatment of pain. As a result of our screening efforts, we identified tetrahydrothienopyridine 4 as an inhibitor of icilin-induced calcium influx in CHO cells expressing recombinant rat TRPM8. Exploration of the structure-activity relationships of 4 led to the identification of a potent and orally bioavailable TRPM8 antagonist, tetrahydroisoquinoline 87. Compound 87 demonstrated target coverage in vivo after oral administration in a rat pharmacodynamic model measuring the prevention of icilin-induced wet-dog shakes (WDS).
Asunto(s)
Analgésicos/síntesis química , Piperidinas/síntesis química , Canales Catiónicos TRPM/antagonistas & inhibidores , Administración Oral , Analgésicos/química , Analgésicos/farmacología , Animales , Células CHO , Calcio/metabolismo , Cricetinae , Cricetulus , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Piperidinas/química , Piperidinas/farmacología , Pirimidinonas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of trisubstituted pyrimidines were synthesized to improve aqueous solubility of our first TRPV1 clinical candidate (1; AMG 517), while maintaining potent TRPV1 inhibitory activity. Structure-activity and structure-solubility studies led to the identification of compound 26. The aqueous solubility of 26 (>or=200microg/mL, 0.01 HCl; 6.7microg/mL, phosphate buffered saline (PBS); 150microg/mL, fasted-state simulated intestinal fluid (SIF)) was significantly improved over 1. In addition, compound 26 was found to be orally bioavailable (rat F(oral)=24%) and had potent TRPV1 antagonist activity (capsaicin IC(50)=1.5nM) comparable to that of 1.
Asunto(s)
Pirimidinas/síntesis química , Pirimidinas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Benzotiazoles/química , Benzotiazoles/farmacología , Células CHO , Capsaicina/antagonistas & inhibidores , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Concentración de Iones de Hidrógeno , Piperazinas/síntesis química , Piperazinas/farmacología , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Solubilidad/efectos de los fármacos , Relación Estructura-Actividad , Canales Catiónicos TRPV/biosíntesis , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/fisiologíaRESUMEN
Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (>or=200 microg/mL in 0.01 N HCl) and a reduced half-life (rat t1/2 = 3.8 h, dog t1/2 = 2.7 h, monkey t1/2 = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.