RESUMEN

Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.

Asunto(s)

Ácidos Carboxílicos/química , Glucurónidos/química , Hipertensión Pulmonar/tratamiento farmacológico , Guanilil Ciclasa Soluble/metabolismo , Vasodilatadores/química , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Glucurónidos/administración & dosificación , Glucurónidos/farmacocinética , Humanos , Masculino , Metaboloma , Modelos Moleculares , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Unión Proteica , Ratas Sprague-Dawley , Transducción de Señal , Relación Estructura-Actividad , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacocinética

RESUMEN

The pharmacokinetics (PK), metabolism, excretion, mass balance, and tissue distribution of [14 C]praliciguat were evaluated following oral administration of a 3-mg/kg dose in Sprague-Dawley rats and in a quantitative whole-body autoradiography (QWBA) study conducted in male Long-Evans rats. Plasma Tmax was 1 hour and the t1/2 of total plasma radioactivity was 23.7 hours. Unchanged praliciguat accounted for 87.4%, and a minor metabolite (N-dealkylated-praliciguat) accounted for 7.6% of the total radioactivity in plasma through 48 hours (AUC0-48 ). Tissues with the highest exposure ratios relative to plasma were liver, intestines, adrenal gland, and adipose, and those with the lowest values were seminal vesicle, blood, CNS tissues, lens of the eye, and bone. Most of the [14 C]praliciguat-derived radioactivity was excreted within 48 hours after oral administration. Mean cumulative recovery of the administered radioactivity in urine and feces over 168 hours was 3.7% and 95.7%, respectively. Unchanged praliciguat was not quantifiable in urine or bile of cannulated rats; however, based on the total radioactivity in these fluids, a minimum of approximately 82% of the orally administered dose was absorbed. [14 C]Praliciguat was metabolized via oxidative and glucuronidation pathways and the most abundant metabolites recovered in bile were praliciguat-glucuronide and hydroxy-praliciguat-glucuronide. These results indicate that praliciguat had rapid absorption, high bioavailability, extensive tissue distribution, and elimination primarily via hepatic metabolism.

Asunto(s)

Pirazoles/farmacocinética , Pirimidinas/farmacocinética , Animales , Bilis/metabolismo , Heces/química , Masculino , Pirazoles/sangre , Pirazoles/orina , Pirimidinas/sangre , Pirimidinas/orina , Ratas Long-Evans , Ratas Sprague-Dawley , Guanilil Ciclasa Soluble , Distribución Tisular

RESUMEN

In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.