Piperidine is a saturated heterocyclic secondary amine that is an important pharmacodynamic group as well as a dominant backbone with a variety of biological activities, such as antibacterial, anti-inflammatory, antiviral, antimalarial, general anesthetic, antidepressant, antioxidant, antiepileptic, antitumor, anticonvulsant, and antihyperlipidemic. Like many nitrogen-containing groups, piperidine is able to form additional interactions with targets, can easily cross cell membranes, solve drug resistance problems, can increase the water solubility of drug molecules, and is the most common group in drug molecule design.
The azepidine ring is one of the most important structural components in drugs. An analysis of the US FDA database of approved drugs shows that 59% of unique small molecule drugs contain nitrogen heterocycles. Among the most prevalent nitrogen ring systems, the drugs containing piperidine rings were the most abundant, followed by pyridine and piperazine.
Marketed drugs
A number of small molecule drugs that have been approved for marketing in recent years also contain piperidine rings. For example, Rimegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist used in the acute treatment of migraine in adults.
Revefenacin is an inhaled muscarinic receptor antagonist, which was launched in the United States in 2018 for the maintenance treatment of chronic obstructive pulmonary disease (COPD).
Lasmiditan succinate is an oral 5-HT1F receptor agonist and is a class of neurologically acting anti-migraine drugs (NAAMA).
Dacomitib, a pan-human epidermal growth factor kinase inhibitor, was first marketed in the United States in 2018 as a first-line oral treatment for metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or 21 L858R exon substitution mutations.
Drug structure optimization
Many of the drugs under development also contain piperidine rings as pharmacodynamic groups that play an important role in enhancing the interaction with the target and improving the pharmacokinetic properties.
1. piperidine ring increases the water solubility of the drug
In addition to being part of the drug's pharmacodynamic group, piperidines have been used to increase the water solubility of the drug.
Since the pKa of piperidine itself is 11.22, the pKa of n-alkylated piperidine is about 9.5. Installing piperidine rings has been routinely used to increase the water solubility of drugs. For example, 4-aminoquinazoline 46 is a potent kinase insertion domain receptor (KDR) inhibitor but has poor solubility (0.7 μM). A basic piperidine ring was installed on the side chain to replace the triazole, which resulted in a 500-fold increase in solubility (330 μM) at pH 7.4 (physiological acidity).
2. Piperidine ring solves the problem of drug resistance
Pgp (permeability glycoprotein) is the most common drug efflux transport protein, which is often overexpressed in tumor cells and is one of the causes of multidrug resistance. Half of the marketed drugs are Pgp substrates.
One strategy to address the Pgp problem is to improve the log P of the drug to reduce penetration into the lipid bilayer. The tetracyclic compound48 is a chemotherapeutic drug that has resulted in cytotoxic resistance due to its use as a Pgp substrate.48 The Mannich reaction of 48 was obtained with a modified 3-aminomethylpiperidine derivative.49 This structural change gives the piperidine compound activity against tumor cells.
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