Synthesis and structure-activity relationship of a novel sulfone series of TNF-alpha converting enzyme inhibitors.
Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-[[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl]-4-pyrrolidinecarboxamide) exhibited IC50 values of < 1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP-1, -2, -9 and -13 and was orally bioavailable with an F value of 46% in mice.
Xue
Chu-Biao
CB
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. cxue@incyte.com
Chen
Xiao-Tao
XT
He
Xiaohua
X
Roderick
John
J
Corbett
Ronald L
RL
Ghavimi
Bahman
B
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Qian
Mingxin
M
Ribadeneira
Maria D
MD
Vaddi
Krishna
K
Trzaskos
James
J
Newton
Robert C
RC
Duan
James J-W
JJ
Decicco
Carl P
CP
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D011480:Protease Inhibitors; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat