Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX).
Autotaxin (ATX) is a secreted soluble enzyme that generates lysophosphatidic acid (LPA) through its lysophospholipase D activity. Because of LPA's role in neoplastic diseases, ATX is an attractive therapeutic target due to its involvement in LPA biosynthesis. Here we describe the SAR of ATX inhibitor, VPC8a202, and apply this SAR knowledge towards developing a high potency inhibitor. We found that electron density in the pyridine region greatly influences activity of our inhibitors at ATX.
University of Virginia, Department of Chemistry, Charlottesville, VA 22904, USA. je5y@virginia.edu
James E
JE
East
Andrew J
AJ
Kennedy
Jose L
JL
Tomsig
Alexandra R
AR
De Leon
Kevin R
KR
Lynch
Timothy L
TL
Macdonald
D000970:Antineoplastic Agents / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D008246:Lysophospholipids / Q000096:biosynthesis; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives*; D000099189:Lysophospholipase D
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011725:Pyridines; D011755:Pyrophosphatases; D014443:Tyrosine; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid