title: Synthesis and structure-activity relationships of beta- and alpha-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy.
abstract: alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Piperidine-alpha-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.
authors.affiliation: Pfizer Research, 4901 Searle Parkway, Skokie, IL 60077, USA. dbecke3@luc.edu
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Becker
authors.forename: Clara I
authors.initials: CI
authors.lastname: Villamil
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Barta
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Bedell
authors.forename: Terri L
authors.initials: TL
authors.lastname: Boehm
authors.forename: Gary A
authors.initials: GA
authors.lastname: Decrescenzo
authors.forename: John N
authors.initials: JN
authors.lastname: Freskos
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Getman
authors.forename: Susan
authors.initials: S
authors.lastname: Hockerman
authors.forename: Robert
authors.initials: R
authors.lastname: Heintz
authors.forename: Susan Carol
authors.initials: SC
authors.lastname: Howard
authors.forename: Madeleine H
authors.initials: MH
authors.lastname: Li
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: McDonald
authors.forename: Chris P
authors.initials: CP
authors.lastname: Carron
authors.forename: Chris L
authors.initials: CL
authors.lastname: Funckes-Shippy
authors.forename: Pramod P
authors.initials: PP
authors.lastname: Mehta
authors.forename: Grace E
authors.initials: GE
authors.lastname: Munie
authors.forename: Craig A
authors.initials: CA
authors.lastname: Swearingen
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000401:mortality; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C505981:N-hydroxy-4-((4-(phenylthio)phenyl)sulfonyl)-1-(2-propynyl)-4-piperidinecarboxamide; D010880:Piperidines; D013450:Sulfones; D017239:Paclitaxel