Organic Building Blocks: Piperidine-Based Drug Discovery

Piperidine is a nitrogen-containing heterocyclic compound that is commonly found in biologically active natural products, such as the broad-spectrum anti-convulsant Piperine, the anti-malaria active ingredient Febrifugine, the immunosuppressant Rapamycin, and the antibiotic Cycloheximide (Fig. 1). In the field of medicine, piperidine is an important pharmacophore, and its derivatives have a wide range of pharmacological activities such as anti-cancer, antibacterial, anti-inflammatory, antiviral, antimalarial, and antipsychotic, which makes piperidine a favored dominant scaffold in drug synthesis. Molecular blocks containing piperidine are also frequently used in the synthesis of small drug molecules.

Fig. 1. Natural products containing piperidine structures.

Structural Features of Piperidine

Nitrogen-containing heterocyclic is one of the most common and important constituent structures in drugs. An analysis of the structure of drugs approved by the FDA showed that 59% of small molecule drugs contain nitrogen-containing heterocyclic scaffolds. And the largest proportion is piperidine drugs, followed by pyridine and piperazine. Further analysis of drugs containing piperidine shows that the number of drug molecules containing substituents at N1- and C4- sites is the largest, accounting for 86% and 58%, respectively, and that at C2- and C3- sites accounts for 33% and 19%, respectively. Only a few drugs have substituents at C5- and C6- sites. Among all these substitution modes, the number of double substitution and single substitution is the largest, accounting for 61% and 21% respectively.

Marketed Drugs Containing Piperidines

Currently, dozens of drug molecules containing piperidine have been approved for the treatment of a variety of diseases, and the piperidine structure (Apixaban, Lenalidomide, and Ibrutinib) is contained in the top three chemical molecules by global sales volume in 2021 (Fig. 2). Other drug molecules such as Raloxifene, a second-generation selective estrogen receptor modulator (SERM), are used to treat breast cancer; Donepezil, an anti-Alzheimer's drug, has a significant effect on patients suffering from apathy; Rimegepant, an oral calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for the acute treatment of migraine with or without aura in adults (Fig. 2).

Fig. 2. Examples of marketed drugs containing piperidines.

Drugs Containing Piperidine in Development

Introducing piperidine into drug molecules or using piperidine to replace other groups plays an important role in enhancing the interaction between drug molecules and targets and improving the pharmacokinetic properties, which is also one of the common strategies applied for new drug development. For example, in 2020, Takeda Pharmaceutical reported the discovery process of GPR40 complete agonist SCO-267. They first analyzed the structure of GPR40 complete agonist in the literature and synthesized compound 1 through preliminary optimization. In order to improve the physicochemical properties of the compound, they replaced the aromatic linking structure of compound 1 with the saturated piperidine group to obtain compound 2, which greatly improved the excitatory activity of the compound. Subsequently, the structure of compound 2 was further modified to find SCO-267 (Fig. 3), which is used in the treatment of diabetes and is currently in the first clinical phase.

Fig. 3. The design process of the SCO-267.

Another example is the powerful selective oral CXCR7 antagonist ACT-1004-1239 reported by Idorsia company in 2020. The research team first obtained the emerging compound through high-throughput screening and then investigated the substituents on the amide bond N. It was found that the substitution of basic amine groups such as morpholine, tetrahydropyrrole, and piperidine significantly improved the potency. Especially when the substituent group is the larger alkyl-substituted piperidine group on N, the molecular potency reaches the highest. The replacement of piperidine at different positions was further optimized to obtain the clinical candidate molecule ACT-1004-1239 (Fig. 4), which is used in anti-tumor studies and is currently in clinical phase Ⅰ.

Fig. 4. The discovery process of ACT-1004-1239.

In addition to drug molecules that have entered the clinic, many active molecules that are still in the stage of development also contain piperidine units, such as the patent molecule of new PLK4 inhibitor published by Qilu Pharmaceutical, which has the potential to treat cancer. Schrödinger has designed new cohesive heterocyclic compounds containing piperidine structure as WEE1 inhibitors, which can effectively inhibit Cdc2 phosphorylation in cancer cells and have anti-cancer potential (Fig. 5).

Fig. 5. Examples of recently patented molecules containing piperidine structure.

Examples of Commonly Used Piperidines and Their Applications

Piperidine molecular blocks belong to the heterocyclic category. Commonly used piperidine molecular blocks include piperidone, piperidol, piperidinamine, piperidine carboxylic acid and its esters, which are widely used in drug development and synthesis with important market value. The series of products, such as 3-amino-2,6-piperidinedione hydrochloride (24666-56-6) are the raw materials for the synthesis of Lenalidomide and Pomalidomide. The latter two compounds are not only the active ingredients of drugs themselves, but also the commonly used E3 ligand, as an important part of protac drug molecules. 4-piperidinemethanol (6457-49-4) can be used in the synthesis of prostate cancer drug ARV-110 and EGFR mutant inhibitors. 4-amino-1-benzylpiperidine (50541-93-0) can be used in the synthesis of non-small cell lung cancer drug Alectinib and PARP7 inhibitors. 1-acetyl-4-piperidinecarboxylic acid (25503-90-6) can be used to synthesize the anti-schizophrenia drug Paliperidone Palmitate and AM2 receptor inhibitors.

BOC Sciences is a leading supplier of piperidine and its derivatives. We offer a wide range of piperidine products, such as 4-(dimethoxymethyl)piperidine, 2,2,6,6-tetramethylpiperidin-1-ol and 4-fluoropiperidine. We can supply high quality piperidine products with competitive price and prompt delivery. We also offer custom synthesis services for piperidine and its derivatives, allowing customers to tailor our products to meet specific requirements.

References

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2. Vitaku, E. et al. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57: 10257-10274.
3. Furukawa, H. et al. Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2-Carbamoylphenyl Piperidine Moiety. J. Med. Chem. 2020, 63(18): 10352-10379.
4. Knoepfel, T. et al. Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists Using a Biochemical TLR8 Antagonist Competition Assay. J. Med. Chem. 2020, 63(15): 8276-8295.