| Title : Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors - Hu_2018_Bioorg.Med.Chem.Lett_28_3721 |
| Author(s) : 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 |
| Ref : Bioorganic & Medicinal Chemistry Lett , 28 :3721 , 2018 |
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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 EL(HDL) hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters. |
| PubMedSearch : Hu_2018_Bioorg.Med.Chem.Lett_28_3721 |
| PubMedID: 30348490 |
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 (2018)
Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors
Bioorganic & Medicinal Chemistry Lett
28 :3721
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 (2018)
Bioorganic & Medicinal Chemistry Lett
28 :3721