title: Orally active MMP-1 sparing α-tetrahydropyranyl and α-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease.
abstract: α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
authors: Pfizer Research, 700 Chesterfield Village Parkway, St. Louis, Missouri 63198, USA. dbecke3@luc.edu
authors: Daniel P
authors: DP
authors: Becker
authors: Thomas E
authors: TE
authors: Barta
authors: Louis J
authors: LJ
authors: Bedell
authors: Terri L
authors: TL
authors: Boehm
authors: Brian R
authors: BR
authors: Bond
authors: Jeffery
authors: J
authors: Carroll
authors: Chris P
authors: CP
authors: Carron
authors: Gary A
authors: GA
authors: Decrescenzo
authors: Alan M
authors: AM
authors: Easton
authors: John N
authors: JN
authors: Freskos
authors: Chris L
authors: CL
authors: Funckes-Shippy
authors: Marcia
authors: M
authors: Heron
authors: Susan
authors: S
authors: Hockerman
authors: Carol Pearcy
authors: CP
authors: Howard
authors: James R
authors: JR
authors: Kiefer
authors: Madeleine H
authors: MH
authors: Li
authors: Karl J
authors: KJ
authors: Mathis
authors: Joseph J
authors: JJ
authors: McDonald
authors: Pramod P
authors: PP
authors: Mehta
authors: Grace E
authors: GE
authors: Munie
authors: Teresa
authors: T
authors: Sunyer
authors: Craig A
authors: CA
authors: Swearingen
authors: Clara I
authors: CI
authors: Villamil
authors: Dean
authors: D
authors: Welsch
authors: Jennifer M
authors: JM
authors: Williams
authors: Ying
authors: Y
authors: Yu
authors: Jun
authors: J
authors: Yao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D002417:Cattle; D018360:Crystallography, X-Ray; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy; D008252:Macaca fascicularis; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C552708:1-cyclopropyl-N-hydroxy-4-(4-(4-(trifluoromethoxy)phenoxy)phenylsulfonyl)piperidine-4-carboxamide; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C552707:N-hydroxy-1-(2-methoxyethyl)-4-((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)piperidine-4-carboxamide; C552706:N-hydroxy-4-((4-(4-(trifluoromethyl)phenoxy)phenyl)sulfonyl)tetrahydro-2H-pyran-4-carboxamide; D010880:Piperidines; D011714:Pyrans; D013450:Sulfones