Aldrich ChemFiles 2005, 5.5, 1.

Aldrich ChemFiles 2005, 5.5, 1.


Sigma-Aldrich is pleased to offer the third installment of our Privileged Structures ChemFiles. This piece will focus on the piperazine scaffold. We will discuss application data, Sigma-Aldrich building blocks that have been highlighted in the recent literature, and the piperazine products that Sigma-Aldrich offers. If you do not see a particular product listed or have a product suggestion, please email us at DrugDiscovery@sial.com. If you did not receive the previous installments of the Privileged Structures ChemFiles, you may download a copy at sigma-aldrich.com/chemfiles.

Privileged Structures are defined as molecules that are capable of binding to multiple receptors with high affinity. In order for a scaffold to be considered privileged, a substructure needs to represent a molecule’s core element and make up a significant portion of its total mass. The main function of privileged structures is to provide a way for medicinal chemists to build a library based on one core scaffold and screen it against an assortment of different receptors.1

The piperazine scaffold has been classified as a privileged structure and is frequently found in biologically active compounds across a number of different therapeutic areas.2 Some of these therapeutic areas include antifungals, antidepressants, antiviral, and serotonin receptor (5-HT) antagonists/agonists.

The therapeutic area that is the subject of intense research is the 5-HT receptors. These receptors belong to the G-protein-coupled receptor (GPCR) superfamily and represent the molecular target for over 45% of all marketed drugs. It is estimated that one-third of all pharmaceutical research is focused on these receptors. This selectivity of piperazines towards GPCRs has been attributed to its basicity.3 Recent SAR studies by Richardson et al. also demonstrated that increasing the size of the ortho substituent resulted in an increase in binding affinity and functional potency.4

(Ref. 5)

(Ref. 6)

(Ref. 7)

(Ref. 8)

Recent literature has highlighted piperazine building blocks that are available from Sigma-Aldrich. Two examples are 1-(2-cyanophenyl)piperazine4 (Cat No 56,718-3) and 1-Boc- 4-(2-formyl phenyl)piperazine10 (Cat No 65,151-6). Both compounds have been used in the synthesis of melanocortin subtype-4 receptor (MC4R) agonists. MC4R is located in the hypothalamus and helps to regulate metabolism, feeding and reproductive behavior. Agonists to these receptors have shown to decrease feeding behaviors.9

(Cat No 56,718-3)(Ref. 4)

(Cat No 65,151-6)(Ref. 10)

Sigma-Aldrich has a large selection of piperazine compounds that can be used as building blocks for organic synthesis and medicinal chemistry. Listed on the following pages are some of the piperazines that are available from Sigma- Aldrich. For a complete list of piperazines, please visit our Web site at sigma-aldrich.com/drugdiscovery.

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  1. D. A. Horton et al. Chem. Rev. 2003, 103, 893–930.
  2. M. Berkheij et al. Tetrahedron Lett. 2005, 15, 2369–2371.
  3. A. O. Stewart et al. J. Med. Chem. 2004, 47, 2348–2355.
  4. T. I. Richardson et al. J. Med. Chem. 2004, 47, 744–755.
  5. Mead Johnson and Company., US-4338317 1982.
  6. EGYT., US-3865828 1975.
  7. Janssen Pharmaceutica N.V., US-4250176 1981.
  8. Ferrer Internacional, S.A., US-4883797 1989.
  9. C. Fotsch et al. Bioorg. Med. Chem. Lett. 2005, 15, 1623–1627.
  10. B. Dyck et al. Bioorg. Med. Chem. Lett. 2003, 13, 3793–3796.

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