title: Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE): discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1' substituents.
abstract: Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. zhonghui.lu@bms.com
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Lu
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ott
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Krishna
authors.initials: K
authors.lastname: Vaddi
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: David D
authors.initials: DD
authors.lastname: Christ
authors.forename: James
authors.initials: J
authors.lastname: Trzaskos
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000737:chemistry*; D001682:Biological Availability; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001572:Benzofurans; D006877:Hydroxamic Acids; D007093:Imidazoles; D007211:Indoles; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C118531:pyrazolopyridine; C030374:indole; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat; C105430:benzofuran