178445-83-5Relevant articles and documents
Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity
Bajaj, Thomas,Bracher, Andreas,Charalampidou, Anna,Gassen, Nils C.,Geiger, Thomas M.,Hausch, Felix,Heymann, Tim,Kolos, Jürgen,Merz, Stephanie,Meyners, Christian,Purder, Patrick L.,Taubert, Martha C.,Voll, Andreas M.,Wessig, Pablo
, p. 13257 - 13263 (2021)
Subtype selectivity represents a challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive drug target. The most advanced FKBP51 ligands of the SAFit class are highly selective vs. FKBP52 but poorly discriminate against the homologs and off-targets FKBP12 and FKBP12.6. During a macrocyclization pilot study, we observed that many of these macrocyclic analogs have unanticipated and unprecedented preference for FKBP51 over FKBP12 and FKBP12.6. Structural studies revealed that these macrocycles bind with a new binding mode featuring a transient conformation, which is disfavored for the small FKBPs. Using a conformation-sensitive assay we show that this binding mode occurs in solution and is characteristic for this new class of compounds. The discovered macrocycles are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 on IKKα. Our findings provide a new chemical scaffold for improved FKBP51 ligands and the structural basis for enhanced selectivity.
Natural scaffolds-inspired synthesis of CF3-substituted macrolides enabled by Rh-catalyzed C–H alkylation macrocyclization
Bi, Tongyu,Li, Jia,Lin, Zhenyang,Tang, Bixi,Xu, Xin,Xu, Yi,Yang, Qing,Yang, Weibo,Zang, Yi
, (2021/11/17)
The development of innovative strategies and methods to provide natural product-like macrocycles not accessible by biosynthesis, but endowed with novel bioactivities and simplified structure, is highly desirable. Inspired by the key scaffolds of rapamycin
NEUROPROTECTIVE COMPOUNDS AND METHODS OF USE THEREOF
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Paragraph 00319, (2021/04/10)
The present disclosure provides neuroprotective compounds along with their use in treating disease such as Parkinson's disease (PD). The compounds can be used as inhibitors for Parthanatos Associated AIF (apoptosis-inducing factor) Nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF).
PROTEIN-BINDING COMPOUNDS
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Paragraph 0521; 0528, (2020/05/19)
The technology relates in part to compounds that bind to proteins. In certain examples, the compounds can bind to proteins that bind to rapamycin. In some examples, the compounds can bind to cellular proteins, and/or variant forms of cellular proteins, th
Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12
Bols, Mikael,Diness, Frederik,J?rgensen, Frederik P.,Madsen, Daniel,Meldal, Morten,Olsen, Jakob V.,Palmer, Daniel,Roux, Milena E.,Schoffelen, Sanne
, (2020/03/10)
On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticle-encoded PEGA1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double
Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35
Atack, Thomas C.,Raymond, Donald D.,Blomquist, Christa A.,Pasaje, Charisse Flerida,McCarren, Patrick R.,Moroco, Jamie,Befekadu, Henock B.,Robinson, Foxy P.,Pal, Debjani,Esherick, Lisl Y.,Ianari, Alessandra,Niles, Jacquin C.,Sellers, William R.
, p. 2131 - 2138 (2020/12/17)
FK506-binding protein 35, FKBP35, has been implicated as an essential malarial enzyme. Rapamycin and FK506 exhibit antiplasmodium activity in cultured parasites. However, due to the highly conserved nature of the binding pockets of FKBPs and the immunosuppressive properties of these drugs, there is a need for compounds that selectively inhibit FKBP35 and lack the undesired side effects. In contrast to human FKBPs, FKBP35 contains a cysteine, C106, adjacent to the rapamycin binding pocket, providing an opportunity to develop targeted covalent inhibitors of Plasmodium FKBP35. Here, we synthesize inhibitors of FKBP35, show that they directly bind FKBP35 in a model cellular setting, selectively covalently modify C106, and exhibit antiplasmodium activity in blood-stage cultured parasites.
MULTIMERIC PIPERIDINE DERIVATIVES
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Page/Page column 131; 132; 134, (2019/07/13)
The technology relates in part to compounds that bind to multimeric ligand binding regions, referred to herein as "multimeric compounds." In certain examples, the multimeric compounds provided herein bind to and multimerize polypeptides that bind to rimiducid, such as for example, chimeric polypeptides that comprise FKBP12 polypeptide variant regions. Multimeric compounds provided include those having a structure of Formula I. Where A, Z, Y, Z' and A' moieties are described herein.
Synthetic process of homodimer of FKBP ligand
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Paragraph 0030; 0035; 0036, (2019/05/28)
The invention discloses a synthesis process of homodimer of FKBP ligand and belongs to an improved synthesis process of AP1903, wherein the homodimer of FKBP ligand refers to AP1903. According to theoptimized route of the synthesis process chooses, (S)-piperidine-2-methyl formate is connected to the compound Cpd9' as selected, an acid Cpd6' obtained after ester hydrolysis is easier to be purified by post-treatment purification, and precipitation or extraction treatment can be chosen by the post-treatment purification. Although the total reaction steps of the synthetic route in the prior literature are the same as the optimized route of the invention, the synthetic route in the prior literature belongs to the vertical route, and the post-treatment of the fifth, sixth and eighth steps requires column chromatography, thereby leading to a higher research and development cost. The optimized AP1903 synthetic route belongs to the parallel route, and the post-treatment is simpler and more advantageous for separation and purification, so that the cost of research and development is relatively low and the economic benefit is obviously superior to that of the synthetic route in the prior art.
An Inexpensive and Scalable Synthesis of Shld
J?rgensen, Frederik Pr?stholm,Bols, Mikael
, p. 6050 - 6055 (2018/05/24)
A synthesis of the important FKBP ligand Shld is reported. The synthesis avoids stoichiometric use of expensive and chiral reagents, maintains enantioselectivity and provides a high overall yield (39%). The main features in the method are enantioselective alkylation for preparation of the phenyl acetic acid moiety (building block A), catalytic enantioselective reduction for obtaining the chiral diaryl-1-propanol (building block C), and direct acylation of S-pipecolic tartrate rather than use of expensive Fmoc-pipecolic acid. The assembly of the building blocks A-C is reversed in comparison to previous synthesis, which also eliminates the need for protective groups.
Synthesis and biological evaluation of chalcone, dihydrochalcone, and 1,3-diarylpropane analogs as anti-inflammatory agents
Vijaya Bhaskar Reddy, Mopur,Hung, Hsin-Yi,Kuo, Ping-Chung,Huang, Guan-Jhong,Chan, Yu-Yi,Huang, Shiow-Chyn,Wu, Shwu-Jen,Morris-Natschke, Susan L.,Lee, Kuo-Hsiung,Wu, Tian-Shung
, p. 1547 - 1550 (2017/03/17)
Twenty-one chalcones were prepared via aldol condensation and subsequent reduction of these compound led to the corresponding dihydrochalcone and 1,3-diphenylpropane derivatives. The synthetic products were examined for their effects on NO inhibition in L
