Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT).
The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide (8), inhibited ADAMTS-5 with IC(50) = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds 8 and 15f inhibited aggrecanase-mediated (374)ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1β/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.
ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, United States. hongfeng.x.deng@gsk.com
Hongfeng
H
Deng
Heather
H
O'Keefe
Christopher P
CP
Davie
Kenneth E
KE
Lind
Raksha A
RA
Acharya
G Joseph
GJ
Franklin
Jonathan
J
Larkin
Rosalie
R
Matico
Michael
M
Neeb
Monique M
MM
Thompson
Thomas
T
Lohr
Jeffrey W
JW
Gross
Paolo A
PA
Centrella
Gary K
GK
O'Donovan
Katie L Sargent
KL
Bedard
Kurt
K
van Vloten
Sibongile
S
Mataruse
Steven R
SR
Skinner
Svetlana L
SL
Belyanskaya
Tiffany Y
TY
Carpenter
Todd W
TW
Shearer
Matthew A
MA
Clark
John W
JW
Cuozzo
Christopher C
CC
Arico-Muendel
Barry A
BA
Morgan
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071116:ADAMTS5 Protein; D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D062126:Databases, Chemical; D010450:Endopeptidases / Q000378:metabolism; D000939:Epitopes; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000096926:Benzenesulfonamides
D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; D053674:Aggrecans; D010450:Endopeptidases; D000939:Epitopes; D006025:Glycosaminoglycans; D054852:Small Molecule Libraries; D013449:Sulfonamides; D014227:Triazines; C576400:N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide; D000096926:Benzenesulfonamides; C121532:ADAMTS5 protein, human; C083641:aggrecanase