P7C3

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P7C3
P7C3 structure.png
Identifiers
  • 1-anilino-3-(3,6-dibromocarbazol-9-yl)propan-2-ol
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H18Br2N2O
Molar mass 474.196 g·mol−1
3D model (JSmol)
  • c4ccccc4NCC(O)Cn2c1ccc(Br)cc1c(c3)c2ccc3Br
  • InChI=1S/C21H18Br2N2O/c22-14-6-8-20-18(10-14)19-11-15(23)7-9-21(19)25(20)13-17(26)12-24-16-4-2-1-3-5-16/h1-11,17,24,26H,12-13H2 X mark.svgN
  • Key:FZHHRERIIVOATI-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

P7C3 (pool 7, compound 3) is a drug related to latrepirdine (dimebon) which has neuroprotective and proneurogenic effects and may be potentially useful for the treatment of Alzheimer's disease and similar neurodegenerative disorders. The pharmacological effects of P7C3 in vitro resemble those of endogenous proneurogenic peptides such as fibroblast growth factor 1 (FGF-1), and the proneurogenic activity of P7C3 was around thirty times that of latrepirdine when they were compared in mice. P7C3 was chosen for further animal studies on the basis of favorable pharmacokinetic factors, such as its high oral bioavailability and long duration of action, but several other related compounds showed similar activity such as the more potent fluorinated analogue P7C3A20 which is up to ten times stronger again, and the methoxy analogue P7C3-OMe, for which it was determined that the (R) enantiomer is the active form. [1]

P7C3A20 and (R)-P7C3-OMe P7C3 derivatives.png
P7C3A20 and (R)-P7C3-OMe

The mechanism of action of the P7C3 series of compounds involves activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme responsible for the transformation of nicotinamide into nicotinamide adenine dinucleotide (NAD). [2] By activating NAMPT, the P7C3 compounds result in an increase in intracellular levels of NAD. [2]

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

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<span class="mw-page-title-main">ADP-ribosylation</span> Addition of one or more ADP-ribose moieties to a protein.

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.

NAD<sup>+</sup> kinase Enzyme

NAD+ kinase (EC 2.7.1.23, NADK) is an enzyme that converts nicotinamide adenine dinucleotide (NAD+) into NADP+ through phosphorylating the NAD+ coenzyme. NADP+ is an essential coenzyme that is reduced to NADPH primarily by the pentose phosphate pathway to provide reducing power in biosynthetic processes such as fatty acid biosynthesis and nucleotide synthesis. The structure of the NADK from the archaean Archaeoglobus fulgidus has been determined.

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<span class="mw-page-title-main">Nicotinamide phosphoribosyltransferase</span> Protein-coding gene in the species Homo sapiens

Nicotinamide phosphoribosyltransferase, formerly known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin for its extracellular form (eNAMPT), is an enzyme that in humans is encoded by the NAMPT gene. The intracellular form of this protein (iNAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide to nicotinamide mononucleotide (NMN) which is responsible for most of the NAD+ formation in mammals. iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present. eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4, that promotes B cell maturation, and that inhibits neutrophil apoptosis.

<span class="mw-page-title-main">Nicotinamide-nucleotide adenylyltransferase</span>

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<span class="mw-page-title-main">NMNAT1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">NNMT</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">NMNAT2</span> Protein-coding gene in the species Homo sapiens

Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an enzyme that in humans is encoded by the NMNAT2 gene.

Charles Brenner is the inaugural Alfred E Mann Family Foundation Chair of the Department of Diabetes & Cancer Metabolism at the Beckman Research Institute of the City of Hope National Medical Center. Brenner previously held the Roy J. Carver Chair in Biochemistry and was head of biochemistry at the University of Iowa.

<span class="mw-page-title-main">Nicotinamide riboside</span> Chemical compound

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<span class="mw-page-title-main">Nicotinamide mononucleotide</span> Chemical compound

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<span class="mw-page-title-main">SARM1</span> Protein-coding gene in the species Homo sapiens

Sterile alpha and TIR motif containing 1 Is an enzyme that in humans is encoded by the SARM1 gene. It is the most evolutionarily conserved member of the Toll/Interleukin receptor-1 (TIR) family. SARM1's TIR domain has intrinsic NADase enzymatic activity that is highly conserved from archaea, plants, nematode worms, fruit flies, and humans. In mammals, SARM1 is highly expressed in neurons, where it resides in both cell bodies and axons, and can be associated with mitochondria.

References

  1. Pieper AA, Xie S, Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE, Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan KS, Naidoo J, Melito L, Hsieh J, De Brabander J, Ready JM, McKnight SL (July 2010). "Discovery of a proneurogenic, neuroprotective chemical". Cell. 142 (1): 39–51. doi:10.1016/j.cell.2010.06.018. PMC   2930815 . PMID   20603013.
  2. 1 2 Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J, Yadavalli S, Mirzaei H, Pieper AA, Ready JM, McKnight SL (2014). "P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage". Cell. 158 (6): 1324–34. doi:10.1016/j.cell.2014.07.040. PMC   4163014 . PMID   25215490.