Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Schnute
Mark E
ME
Global Research and Development, Pfizer Inc., 700 Chesterfield Parkway West, St. Louis, MO 63017, USA. mark.e.schnute@pfizer.com
O'Brien
Patrick M
PM
Nahra
Joe
J
Morris
Mark
M
Howard Roark
W
W
Hanau
Cathleen E
CE
Ruminski
Peter G
PG
Scholten
Jeffrey A
JA
Fletcher
Theresa R
TR
Hamper
Bruce C
BC
Carroll
Jeffery N
JN
Patt
William C
WC
Shieh
Huey S
HS
Collins
Brandon
B
Pavlovsky
Alexander G
AG
Palmquist
Katherine E
KE
Aston
Karl W
KW
Hitchcock
Jeffrey
J
Rogers
Michael D
MD
McDonald
Joseph
J
Johnson
Adam R
AR
Munie
Grace E
GE
Wittwer
Arthur J
AJ
Man
Chiu-Fai
CF
Settle
Steven L
SL
Nemirovskiy
Olga
O
Vickery
Lillian E
LE
Agawal
Arun
A
Dyer
Richard D
RD
Sunyer
Teresa
T
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D055808:Drug Discovery; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000188:drug therapy*; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
D061965:Matrix Metalloproteinase Inhibitors; D010848:Picolinic Acids; D011480:Protease Inhibitors; D013777:Tetrazoles; D053509:Matrix Metalloproteinase 13; D015032:Zinc