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J Med Chem ; 62(20): 9270-9280, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31532662


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.

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/metabolismo
J Med Chem ; 61(24): 11209-11220, 2018 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-30500190


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.

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/farmacocinética
J Med Chem ; 59(11): 5356-67, 2016 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-27167608


Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tiazoles/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química