Orally active MMP-1 sparing α-tetrahydropyranyl and α-piperidinyl sulfone matrix metalloproteinase (MMP) inhibitors with efficacy in cancer, arthritis, and cardiovascular disease.
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.
Becker
Daniel P
DP
Pfizer Research, 700 Chesterfield Village Parkway, St. Louis, Missouri 63198, USA. dbecke3@luc.edu
Barta
Thomas E
TE
Bedell
Louis J
LJ
Boehm
Terri L
TL
Bond
Brian R
BR
Carroll
Jeffery
J
Carron
Chris P
CP
Decrescenzo
Gary A
GA
Easton
Alan M
AM
Freskos
John N
JN
Funckes-Shippy
Chris L
CL
Heron
Marcia
M
Hockerman
Susan
S
Howard
Carol Pearcy
CP
Kiefer
James R
JR
Li
Madeleine H
MH
Mathis
Karl J
KJ
McDonald
Joseph J
JJ
Mehta
Pramod P
PP
Munie
Grace E
GE
Sunyer
Teresa
T
Swearingen
Craig A
CA
Villamil
Clara I
CI
Welsch
Dean
D
Williams
Jennifer M
JM
Yu
Ying
Y
Yao
Jun
J
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
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