title: Design, synthesis, and biological activity of novel polycyclic aza-amide FKBP12 ligands.
abstract: 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.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Hudack
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Barta
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Judith
authors.initials: J
authors.lastname: Deal
authors.forename: Liming
authors.initials: L
authors.lastname: Dong
authors.forename: Lorraine K
authors.initials: LK
authors.lastname: Fay
authors.forename: Bradley
authors.initials: B
authors.lastname: Caprathe
authors.forename: Arindam
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Darin
authors.initials: D
authors.lastname: Vanderpool
authors.forename: Christopher
authors.initials: C
authors.lastname: Bigge
authors.forename: Richard
authors.initials: R
authors.lastname: Showalter
authors.forename: Steve
authors.initials: S
authors.lastname: Bender
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Augelli-Szafran
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lunney
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
mesh_terms: 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*
chemical_list: 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