Lubiprostone
[CAS# 136790-76-6]

Identification

• Classification: Biochemical >> Inhibitor >> Transmembrane transporters >> CFTR activator
• Name: Lubiprostone
• Synonyms: 7-[(1R,4R,6R,9R)-4-(1,1-Difluoropentyl)-4-hydroxy-8-oxo-5-oxabicyclo[4.3.0]non-9-yl]heptanoic acid
• Molecular Formula: C₂₀H₃₂F₂O₅
• Molecular Weight: 390.46
• CAS Registry Number: 136790-76-6
• EC Number: 603-977-7
• SMILES: CCCCC([C@]1(CC[C@H]2[C@H](O1)CC(=O)[C@@H]2CCCCCCC(=O)O)O)(F)F

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 532.3±50.0 °C 760 mmHg (Calc.)^*
• Flash point: 275.7±30.1 °C (Calc.)^*
• Index of refraction: 1.486 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P305+P351+P338

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Reproductive toxicity	Repr.	2	H361
Acute toxicity	Acute Tox.	3	H300
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

Lubiprostone is a bicyclic fatty acid derivative belonging to the prostaglandin E₁ (PGE₁) analog class. It was first synthesized and characterized as part of research into prostaglandin-based compounds with ion transport and fluid secretory activity in epithelial tissues. Unlike classical prostaglandins that act primarily through G protein-coupled receptors, lubiprostone’s key mechanism is the activation of specific chloride channels on epithelial cells, which facilitates chloride ion efflux and the subsequent movement of sodium and water into the intestinal lumen. This property led to its development and clinical application as a locally acting intestinal secretagogue for the treatment of chronic constipation disorders.

The discovery of lubiprostone was based on studies investigating derivatives of prostaglandin E₁ that could act on epithelial chloride conductance without eliciting the systemic vasodilatory effects typically associated with prostaglandins. Lubiprostone, formally named (–)-(7R,11R,12R,15R)-9-oxo-7-(p-phenyl-trans-hydroxypropenyl)-11,12-epoxy-13,14-dinor-15-oxo-prost-5-en-1-oic acid, was identified as a compound with high activity in stimulating chloride secretion in intestinal epithelial cells. Its discovery was reported through a combination of synthetic, biochemical, and physiological studies performed in the 1990s and early 2000s, culminating in approval for clinical use in 2006.

Lubiprostone acts primarily by activating type 2 chloride channels (ClC-2) located on the apical membrane of gastrointestinal epithelial cells. Activation of these channels promotes the efflux of chloride ions into the intestinal lumen, which osmotically drives water secretion and softens the stool. The compound acts locally within the intestinal mucosa and has minimal systemic absorption, as demonstrated by pharmacokinetic studies showing low plasma concentrations and rapid metabolism. Secondary investigations have also shown that lubiprostone may enhance mucosal barrier function and stimulate bicarbonate secretion, thereby contributing to mucosal protection and improved intestinal physiology. Electrophysiological experiments confirmed that the chloride current induced by lubiprostone is independent of cyclic AMP pathways, distinguishing it mechanistically from secretagogues acting via CFTR channel activation.

Clinically, lubiprostone is approved for the treatment of chronic idiopathic constipation, irritable bowel syndrome with constipation (IBS-C) in adult women, and opioid-induced constipation in adults. It is marketed under trade names such as Amitiza. The efficacy of lubiprostone has been supported by randomized, double-blind, placebo-controlled trials demonstrating improved spontaneous bowel movement frequency, stool consistency, and symptom relief. The drug’s safety profile is characterized by minimal systemic adverse effects, though nausea and diarrhea are reported in a minority of patients. Due to its local mechanism of action, lubiprostone does not produce significant cardiovascular or reproductive system side effects typical of other prostaglandin analogs.

Chemically, lubiprostone retains key structural elements of the prostaglandin E₁ framework, including the cyclopentane ring and the oxygenated side chains, but it features a unique epoxy substitution that confers chemical stability and receptor selectivity. The stereochemistry of its multiple chiral centers is crucial to biological activity, and total synthesis efforts have focused on maintaining correct configuration to preserve efficacy. Its development established a precedent for designing prostaglandin derivatives that act on ion channels rather than classical prostanoid receptors, creating a new pharmacological approach to managing intestinal fluid balance disorders.

References

Cuppoletti J, Malinowska DH, Tewari KP, Li QJ, Sherry AM, Patchen ML, Ueno R (2004) SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. American Journal of Physiology - Cell Physiology 287 C1173–C1183 DOI: 10.1152/ajpcell.00528.2003

Camilleri M, Bharucha AE, Ueno R, Burton D, Thomforde GM, Baxter K, McKinzie S, Zinsmeister AR (2006) Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. American Journal of Physiology - Gastrointestinal and Liver Physiology 290 G942–G947 DOI: 10.1152/ajpgi.00264.2005

Bassil AK, Borman RA, Jarvie EM, McArthur-Wilson RJ, Weston J, Lee K, Sanger GJ (2008) Activation of prostaglandin EP receptors by lubiprostone in rat and human stomach and colon. British Journal of Pharmacology 154 126–135 DOI: 10.1038/bjp.2008.84