Synthesis and SAR of bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors.
Potent and selective bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors were synthesized by a novel convergent route. Selectivity and efficacy versus MMPs and TACE could be controlled by appropriate substitution on the scaffolds and by variation of the P1' group. Select compounds were found to be effective in in vivo models of arthritis.
Zask
A
A
Wyeth-Ayerst Research, 401N. Middletown Road, Pearl River, NY 10965, USA. zaska@wyeth.com
Gu
Y
Y
Albright
J D
JD
Du
X
X
Hogan
M
M
Levin
J I
JI
Chen
J M
JM
Killar
L M
LM
Sung
A
A
DiJoseph
J F
JF
Sharr
M A
MA
Roth
C E
CE
Skala
S
S
Jin
G
G
Cowling
R
R
Mohler
K M
KM
Barone
D
D
Black
R
R
March
C
C
Skotnicki
J S
JS
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000473:pathology; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D002417:Cattle; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat