6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease.
Bioorg Med Chem Lett
; 29(24): 126753, 2019 12 15.
Article
em En
| MEDLINE
| ID: mdl-31679971
ABSTRACT
The oral K+-sparing diuretic amiloride shows anti-cancer side-activities in multiple rodent models. These effects appear to arise, at least in part, through moderate inhibition of the urokinase-type plasminogen activator (uPA, Kiâ¯=â¯2.4⯵M), a pro-metastatic trypsin-like serine protease that is upregulated in many aggressive solid malignancies. In applying the selective optimization of side-activity (SOSA) approach, a focused library of twenty two 6-substituted amiloride derivatives were prepared, with multiple examples displaying uPA inhibitory potencies in the nM range. X-ray co-crystal structures revealed that the potency increases relative to amiloride arise from increased occupancy of uPA's S1ß subsite by the appended 6-substituents. Leading compounds were shown to have high selectivity over related trypsin-like serine proteases and no diuretic or anti-kaliuretic effects in rats. Compound 15 showed anti-metastatic effects in a xenografted mouse model of late-stage lung metastasis.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ativador de Plasminogênio Tipo Uroquinase
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Diuréticos
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Amilorida
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Metástase Neoplásica
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article