Design, synthesis, and evaluation of benzothiadiazepine hydroxamates as selective tumor necrosis factor-alpha converting enzyme inhibitors.
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K(i) = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC(50) = 0.35 microM), while compound 62 was the most active in the WBA (IC(50) = 1.4 microM).
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. robert.cherney@bms.com
Robert J
RJ
Cherney
James J-W
JJ
Duan
Matthew E
ME
Voss
Lihua
L
Chen
Li
L
Wang
Dayton T
DT
Meyer
Zelda R
ZR
Wasserman
Karl D
KD
Hardman
Rui-Qin
RQ
Liu
Maryanne B
MB
Covington
Mingxin
M
Qian
Sandhya
S
Mandlekar
David D
DD
Christ
James M
JM
Trzaskos
Robert C
RC
Newton
Ronald L
RL
Magolda
Ruth R
RR
Wexler
Carl P
CP
Decicco
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013552:Swine; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D001570:Benzodiazepinones; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C474568:N-hydroxy-2-(7-(3-nitrophenoxy)-2,3,4,5-tetrahydrobenzo(1,2,5-f)thiadiazepine-1,1-dioxide)propanamide; C474567:N-hydroxy-2-(7-benzyloxy-2,3,4,5-tetrahydrobenzo(1,2,5-f)thiadiazepine-1,1-dioxide)-4-methylpentanamide; D013841:Thiazepines; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human