2-Aryl-2,2-difluoroacetamide FKBP12 ligands: synthesis and X-ray structural studies.
[structure: see text] 2-Aryl-2,2-difluoroacetamido-proline and pipecolate esters are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest that the fluorine atoms participate in discrete interactions with the Phe36 phenyl ring and the Tyr26 hydroxyl group, with the latter resembling a moderate-to-weak hydrogen bond.
Dubowchik
G M
GM
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5100, Wallingford, Connecticut 06492-7660, USA. gene.dubowchik@bms.com
Vrudhula
V M
VM
Dasgupta
B
B
Ditta
J
J
Chen
T
T
Sheriff
S
S
Sipman
K
K
Witmer
M
M
Tredup
J
J
Vyas
D M
DM
Verdoorn
T A
TA
Bollini
S
S
Vinitsky
A
A
D000081:Acetamides / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D016559:Tacrolimus / Q000737:chemistry* / Q000378:metabolism; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors
D000081:Acetamides; D006845:Hydrocarbons, Fluorinated; D007166:Immunosuppressive Agents; D008024:Ligands; D022061:Tacrolimus Binding Protein 1A; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus