A novel class of ion displacement ligands as antagonists of the αIIbβ3 receptor that limit conformational reorganization of the receptor.
A collection of αIIbβ3 integrin receptor antagonists possessing a unique MIDAS metal ion displacement mechanism of action is presented. Insight into these agents' structure-activity relationships, binding modality, and pharmacokinetic and pharmacodynamic profiles highlight the potential of these small molecule ion displacement ligands as attractive candidates for clinical development.
NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
Jian-kang
JK
Jiang
NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
Joshua G
JG
McCoy
NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
Min
M
Shen
NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
Christopher A
CA
LeClair
NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
Wenwei
W
Huang
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Ana
A
Negri
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
Jihong
J
Li
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
Robert
R
Blue
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
Amanda Weil
AW
Harrington
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
Sarasija
S
Naini
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
George
G
David
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
Won-Seok
WS
Choi
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
Elisabetta
E
Volpi
Proteomics Resource Center, Rockefeller University, New York, NY, United States.
Joseph
J
Fernandez
Touro College of Pharmacy, New York, NY, United States.
Mariana
M
Babayeva
Ekam Imaging, Boston, MA, United States.
Mark A
MA
Nedelman
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Marta
M
Filizola
Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller University, New York, NY, United States.
Barry S
BS
Coller
NIH Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: craigt@mail.nih.gov.
Craig J
CJ
Thomas
D001798:Blood Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007477:Ions / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001798:Blood Proteins; D007477:Ions; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C024875:platelet adhesion inhibitor
Ion displacement ligand; Platelet; αIIbβ3 Integrin receptor