Imidazopyridine Explained

An imidazopyridine is a nitrogen containing heterocycle that is also a class of drugs that contain this same chemical substructure. In general, they are GABA_A receptor agonists, however recently proton pump inhibitors, aromatase inhibitors, NSAIDs and other classes of drugs in this class have been developed as well. Despite usually being similar to them in effect, they are not chemically related to benzodiazepines. As such, GABA_A-agonizing imidazopyridines, pyrazolopyrimidines, and cyclopyrrones are sometimes grouped together and referred to as "nonbenzodiazepines." Imidazopyridines include:

Sedatives

Anxiolytics, sedatives and hypnotics (GABA_A receptor positive allosteric modulators):

• Imidazo[1,2-a]pyridines:
  • Alpidem (original brand name Ananxyl)—an anxiolytic that was withdrawn from the market worldwide in 1995 due to hepatotoxicity.
  • DS-1—a GABA_A receptor positive allosteric modulator selective for the α₄β₃δ subtype, which is not targeted by other GABAergics such as benzodiazepines or other nonbenzodiazepines.^[1]
  • Necopidem—an anxiolytic. It has not found clinical use.
  • Saripidem—a sedative and anxiolytic. It is not used clinically.
  • TP-003—a subtype-selective partial agonist at GABA_A receptors, binding to GABA_A receptor complexes bearing either α₂, α₃ or α₅ subunits, but only showing significant efficacy at α₃.
  • Zolpidem (original brand name Ambien)—a widely used hypnotic. Generic versions are widely available.
• Imidazo[4,5-c]pyridines:
  • Bamaluzole—a GABA_A receptor-agonizing anticonvulsant that was never marketed.^[2]

Antipsychotic

Antipsychotics:

• Imidazo[1,2-a]pyridines:
  • Mosapramine (brand name クレミン, Cremin)—an atypical antipsychotic used in Japan.^[3]

Gastrointestinal

Drugs used for peptic ulcer disease (PUD), GERD and gastroprokinetic agents (motility stimulants):

• Imidazo[1,2-a]pyridines:
  • CJ-033466—an experimental gastroprokinetic acting as a selective 5-HT₄ serotonin receptor partial agonist.^[4]
  • Zolimidine—a gastroprotective agent.^[5]
  • Linaprazan—a potassium-competitive acid blocker which demonstrated similar efficacy as esomeprazole in healing and controlling symptoms of GERD patients with erosive esophagitis.^[6]
  • SCH28080—the prototypical potassium-competitive acid blocker which has not found clinical use because of liver toxicity in animal trials and elevated liver enzyme activity in the serum of human volunteers.^[7]
• Imidazo[4,5-b]pyridines:
  • Tenatoprazole—it blocks the gastric proton pump leading to decline of gastric acid production.

Anti-inflammatories

NSAIDs, analgesics and antimigraine drugs:

• Imidazo[1,2-a]pyridines:
  • Miroprofen—a derivative of propionic acid.
• Imidazo[4,5-b]pyridines:
  • Telcagepant—a calcitonin gene-related peptide receptor antagonist which was in clinical trials as a remedy for migraine. Its development was terminated.^[8]

Cardiovascular

Drugs acting on the cardiovascular system:

• Imidazo[1,2-a]pyridines:
  • Olprinone (loprinone)—a cardiac stimulant.^[9]

Bone

Drugs for treatment of bone diseases:

• Imidazo[1,2-a]pyridines:
  • Minodronic acid (brand names Bonoteo, Recalbon)—a third-generation bisphosphonate used for the treatment of osteoporosis.^[10]

Antineoplastic

Antineoplastic agents:

• Imidazo[1,5-a]pyridines:
  • Fadrozole (brand name Afema)—an aromatase inhibitor.
• Imidazo[4,5-c]pyridines:
  • 3-Deazaneplanocin A—an S-adenosyl-L-homocysteine synthesis inhibitor and histone methyltransferase EZH2 inhibitor.

Antiviral

Directly-acting antiviral agents:

• Imidazo[1,2-a]pyridines:
  • Tegobuvir (GS-9190) - an allosteric, non-nucleoside hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitor targeting the thumb II allosteric site.^[11]

DAergic

• PIP3EA [885446-91-3] D4 agonist supported to have penile erectant properties.

Notes and References

1. Wafford KA, van Niel MB, Ma QP, Horridge E, Herd MB, Peden DR, Belelli D, Lambert JJ . 6 . Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus . Neuropharmacology . 56 . 1 . 182–9 . January 2009 . 18762200 . 10.1016/j.neuropharm.2008.08.004 . 207224202 .
2. Book: David J. Triggle . Dictionary of Pharmacological Agents . Chapman & Hall/CRC . Boca Raton . 1996 . 0-412-46630-9 .
3. Takahashi N, Terao T, Oga T, Okada M . Comparison of risperidone and mosapramine addition to neuroleptic treatment in chronic schizophrenia . Neuropsychobiology . 39 . 2 . 81–5 . 1999 . 10072664 . 10.1159/000026565 . 6554048 .
4. Mikami T, Ochi Y, Suzuki K, Saito T, Sugie Y, Sakakibara M . 5-Amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel and selective 5-hydroxytryptamine4 receptor partial agonist: pharmacological profile in vitro and gastroprokinetic effect in conscious dogs . The Journal of Pharmacology and Experimental Therapeutics . 325 . 1 . 190–9 . April 2008 . 18198343 . 10.1124/jpet.107.133850 . 40500864 .
5. Belohlavek D, Malfertheiner P . The effect of zolimidine, imidazopyridine-derivate, on the duodenal ulcer healing . Scandinavian Journal of Gastroenterology. Supplement . 54 . 44 . 1979 . 161649 .
6. Kahrilas PJ, Dent J, Lauritsen K, Malfertheiner P, Denison H, Franzén S, Hasselgren G . A randomized, comparative study of three doses of AZD0865 and esomeprazole for healing of reflux esophagitis . Clinical Gastroenterology and Hepatology . 5 . 12 . 1385–91 . December 2007 . 17950677 . 10.1016/j.cgh.2007.08.014 . free .
7. Web site: Ravinder Reddy S, Basavaraja HS, Shivaprasad S . Reversible Proton Pump Inhibitors: A Superior Edge — Features. https://web.archive.org/web/20160305125148/http://www.pharmabiz.com/article/detnews.asp?articleid=21265&sectionid=46 . 5 March 2016 . dead . Pharmabiz.com. Saffron Media Pvt. Ltd I. 7 December 2015.
8. Web site: Merck Announces Second Quarter 2011 Financial Results . 6 December 2015 . 12 April 2013 . https://web.archive.org/web/20130412063354/http://www.mercknewsroom.com/press-release/financial-news/merck-announces-second-quarter-2011-financial-results . dead .
9. Uemura Y, Tanaka S, Ida S, Yuzuriha T . Pharmacokinetic study of loprinone hydrochloride, a new cardiotonic agent, in beagle dogs . The Journal of Pharmacy and Pharmacology . 45 . 12 . 1077–81 . December 1993 . 7908977 . 10.1111/j.2042-7158.1993.tb07184.x . 39583447 .
10. Hegde S, Schmidt M . To market, to market—2009. . Annual Reports in Medicinal Chemistry . January 2010 . 45 . 466–537 . 10.1016/s0065-7743(10)45028-9. 9780123809025 .
11. Hebner CM, Han B, Brendza KM, Nash M, Sulfab M, Tian Y, Hung M, Fung W, Vivian RW, Trenkle J, Taylor J, Bjornson K, Bondy S, Liu X, Link J, Neyts J, Sakowicz R, Zhong W, Tang H, Schmitz U . 6 . The HCV non-nucleoside inhibitor Tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function . PLOS ONE . 7 . 6 . e39163 . 2012 . 22720059 . 3374789 . 10.1371/journal.pone.0039163 . 2012PLoSO...739163H . free .