Synthesis and structure-activity relationships of 4-alkynyloxy phenyl sulfanyl, sulfinyl, and sulfonyl alkyl hydroxamates as tumor necrosis factor-alpha converting enzyme and matrix metalloproteinase inhibitors.
A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure-activity relationships, against tumor necrosis factor-alpha (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1' substituent. The sulfonyl derivatives 20-24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25-28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-alpha release in the mouse at 100 mg/kg po.
Venkatesan
Aranapakam M
AM
Wyeth Research, Pearl River, New York 10965, USA. venkata@wyeth.com
Davis
Jamie M
JM
Grosu
George T
GT
Baker
Jannie
J
Zask
Arie
A
Levin
Jeremy I
JI
Ellingboe
John
J
Skotnicki
Jerauld S
JS
Dijoseph
John F
JF
Sung
Amy
A
Jin
Guixian
G
Xu
Weixin
W
McCarthy
Diane Joseph
DJ
Barone
Dauphine
D
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines; D013440:Sulfides; D013450:Sulfones; D013454:Sulfoxides; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse