Design, synthesis, and biological activity of novel polycyclic aza-amide FKBP12 ligands.
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
Hudack
Raymond A
RA
Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Barta
Nancy S
NS
Guo
Chuangxing
C
Deal
Judith
J
Dong
Liming
L
Fay
Lorraine K
LK
Caprathe
Bradley
B
Chatterjee
Arindam
A
Vanderpool
Darin
D
Bigge
Christopher
C
Showalter
Richard
R
Bender
Steve
S
Augelli-Szafran
Corinne E
CE
Lunney
Elizabeth
E
Hou
Xinjun
X
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry; D008024:Ligands; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000737:chemistry; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000577:Amides; D001372:Aza Compounds; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D008024:Ligands; D018696:Neuroprotective Agents; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus