Design, Synthesis, and Biological Activity of Novel Polycyclic Aza-Amide FKBP12 Ligands

Hudack, Raymond A.; Barta, Nancy S.; Guo, Cunlan; Deal, Judith G.; Dong, Liming; Fay, Lorraine K.; Caprathe, Bradley W.; Chatterjee, Arindam; Vanderpool, Darin; Bigge, Christopher F.; Showalter, Richard E.; Bender, Steve; Augelli‐Szafran, Corinne E.; Lunney, Elizabeth A.; Hou, Xinjun

doi:10.1021/jm049161u

Cited by 20 publications

(12 citation statements)

References 22 publications

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“…Two compounds, AG5473 and AG5507, displayed high binding affinity for FKBP12, with 84 nM and 54 nm, respectively (Guo et al, 2000). Further derivatization of this scaffold by interconverting the α-keto-amide to sulfonamides, sulfamides, ureas and α,α-difluoro amides resulted in no or only marginal improvements in affinity (Hudack et al, 2006).…”

Section: Fkbp12 and Fkbp126mentioning

confidence: 99%

FKBP Ligands—Where We Are and Where to Go?

et al. 2018

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In recent years, many members of the FK506-binding protein (FKBP) family were increasingly linked to various diseases. The binding domain of FKBPs differs only in a few amino acid residues, but their biological roles are versatile. High-affinity ligands with selectivity between close homologs are scarce. This review will give an overview of the most prominent ligands developed for FKBPs and highlight a perspective for future developments. More precisely, human FKBPs and correlated diseases will be discussed as well as microbial FKBPs in the context of anti-bacterial and anti-fungal therapeutics. The last section gives insights into high-affinity ligands as chemical tools and dimerizers.

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Section: Fkbp12 and Fkbp126mentioning

confidence: 99%

FKBP Ligands—Where We Are and Where to Go?

et al. 2018

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“…These two compounds are bifunctional in nature and possess two distinct binding domains. These domains are an immunophilin binding region, which binds to FKBP12 (FK506 binding protein), and an effector domain, which mediates the interaction of the drug–immunophilin complex with the secondary protein target . Inhibition of calcineurin and RAFT (rapamycin and FKBP12 target) by these complexes is at the basis of the mechanism for the immunosuppression activity of 1 and 2 , respectively.…”

Section: Introductionmentioning

confidence: 99%

The Alpha Keto Amide Moiety as a Privileged Motif in Medicinal Chemistry: Current Insights and Emerging Opportunities

et al. 2021

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Over the years, researchers in drug discovery have taken advantage of the use of privileged structures to design innovative hit/lead molecules. The α-ketoamide motif is found in many natural products, and it has been widely exploited by medicinal chemists to develop compounds tailored to a vast range of biological targets, thus presenting clinical potential for a plethora of pathological conditions. The purpose of this perspective is to provide insights into the versatility of this chemical moiety as a privileged structure in drug discovery. After a brief analysis of its physical–chemical features and synthetic procedures to obtain it, α-ketoamide-based classes of compounds are reported according to the application of this motif as either a nonreactive or reactive moiety. The goal is to highlight those aspects that may be useful to understanding the perspectives of employing the α-ketoamide moiety in the rational design of compounds able to interact with a specific target.

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“…(S)-1-Fluoro-3-(2-methoxyphenoxy)propan-2-ol (11). To a stirring solution of compound 10 (50 mg, 0.27 mmol) in toluene (1 mL) was added tetra-n-butylammonium fluoride (1.0 M, 1.7 mL), and the mixture was heated to 80 °C for 3 h. The reaction mixture was diluted with H 2 O (15 mL) and then extracted with EtOAc (60 mL).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Guaifenesin Derivatives Promote Neurite Outgrowth and Protect Diabetic Mice from Neuropathy

et al. 2013

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In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (R/S)-guaifenesin (1) was identified as a potent enhancer of neurite outgrowth using an in vitro screen. Its R-enantiomer (R)-1 carried the most biological activity, whereas the S-enantiomer (S)-1 was inactive. Focused structural variations to (R/S)-1 was conducted to identify potentially essential groups for the neurite outgrowth activity. In vivo therapeutic studies indicated that both (R/S)-1 and (R)-1 partially prevented motor nerve conduction velocity slowing in a mouse model of type 1 diabetes. In vitro microsomal assays suggested that compounds (R)-1 and (S)-1 are not metabolized rapidly, and PAMPA assay indicated moderate permeability through the membrane. Findings revealed here could lead to the development of novel drugs for diabetic neuropathy.

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Design, Synthesis, and Biological Activity of Novel Polycyclic Aza-Amide FKBP12 Ligands

Cited by 20 publications

References 22 publications

FKBP Ligands—Where We Are and Where to Go?

FKBP Ligands—Where We Are and Where to Go?

The Alpha Keto Amide Moiety as a Privileged Motif in Medicinal Chemistry: Current Insights and Emerging Opportunities

Guaifenesin Derivatives Promote Neurite Outgrowth and Protect Diabetic Mice from Neuropathy

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