Discovery and validation of a series of aryl sulfonamides as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP).
We report the characterization and optimization of drug-like small molecule inhibitors of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme critical for the regulation of extracellular matrix calcification during bone formation and growth. High-throughput screening (HTS) of a small molecule library led to the identification of arylsulfonamides as potent and selective inhibitors of TNAP. Critical structural requirements for activity were determined, and the compounds were subsequently profiled for in vitro activity and bioavailability parameters including metabolic stability and permeability. The plasma levels following subcutaneous administration of a member of the lead series in rat was determined, demonstrating the potential of these TNAP inhibitors as systemically active therapeutic agents to target various diseases involving soft tissue calcification. A representative member of the series was also characterized in mechanistic and kinetic studies.
Dahl
Russell
R
Conrad Prebys Center for Chemical Genomics, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Sergienko
Eduard A
EA
Su
Ying
Y
Mostofi
Yalda S
YS
Yang
Li
L
Simao
Ana Maria
AM
Narisawa
Sonoko
S
Brown
Brock
B
Mangravita-Novo
Arianna
A
Vicchiarelli
Michael
M
Smith
Layton H
LH
O'Neill
W Charles
WC
Millán
José Luis
JL
Cosford
Nicholas D P
ND
D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D019556:COS Cells; D002114:Calcinosis / Q000517:prevention & control; D002384:Catalysis; D002522:Chlorocebus aethiops; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000469:Alkaline Phosphatase; D011804:Quinolines; D013449:Sulfonamides; C545551:2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C545552:5-bromo-2-methoxy-N-(quinolin-3-yl)benzenesulfonamide