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Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors.

Abstract：

:Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Hu CH,Wang TC,Qiao JX,Haque L,Chen AYA,Taylor DS,Ying X,Onorato JM,Galella M,Shen H,Huang CS,Toussaint N,Li YX,Abell L,Adam LP,Gordon D,Wexler RR,Finlay HJ

doi

10.1016/j.bmcl.2018.10.022

subject

Has Abstract

pub_date

2018-12-15 00:00:00

pages

3721-3725

issue

23-24

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(18)30824-2

journal_volume

28

pub_type

杂志文章

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