title: 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.
abstract: 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.
authors.affiliation: Wyeth Research, Pearl River, New York 10965, USA. venkata@wyeth.com
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Davis
authors.forename: George T
authors.initials: GT
authors.lastname: Grosu
authors.forename: Jannie
authors.initials: J
authors.lastname: Baker
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
authors.forename: John
authors.initials: J
authors.lastname: Ellingboe
authors.forename: Jerauld S
authors.initials: JS
authors.lastname: Skotnicki
authors.forename: John F
authors.initials: JF
authors.lastname: Dijoseph
authors.forename: Amy
authors.initials: A
authors.lastname: Sung
authors.forename: Guixian
authors.initials: G
authors.lastname: Jin
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Diane Joseph
authors.initials: DJ
authors.lastname: McCarthy
authors.forename: Dauphine
authors.initials: D
authors.lastname: Barone
mesh_terms: 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
chemical_list: 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