Linaclotide

SKU: orb1941010

Description

A potent and selective GC-C agonist (Ki=1.23-1.64 nM) that elicits pharmacological effects locally in the gastrointestinal tract; induces a significant increase in fluid secretion, accompanied by a significant increase in intraluminal cGMP levels; has potential for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation.Irritable Bowel Syndrome Approved(In Vitro):Linaclotide inhibits in vitro [125I]-STa binding to intestinal mucosal membranes from wt mice in a concentration-dependent manner. In contrast, [125I]-STa binding to these membranes from GC-C null mice is significantly decreased. After incubation in vitro in jejunal fluid for 30 min, linaclotide is completely degraded. Linaclotide acts on guanylate cyclase-C receptors on the luminal membrane to increase chloride and bicarbonate secretions into the intestine and inhibit the absorption of sodium ions, thus increasing the secretion of water into the lumen and improving defecation; the drug is minimally absorbed into the systemic circulation.\n(In Vivo):Pharmacokinetic analysis shows very low oral bioavailability (0.10%). In intestinal secretion and transit models, linaclotide exhibits significant pharmacological effects in wt, but not in GC-C null mice: induction of increased fluid secretion into surgically ligated jejunal loops is accompanied by the secretion of elevated levels of cyclic guanosine-3',5-monophosphate and accelerated gastrointestinal transit. Linaclotide significantly increases weekly spontaneous bowel movements and complete spontaneous bowel movements (CSBMs) while reducing abdominal pain in patients with chronic constipation.

Key Properties

• CAS Number: 851199-59-2
• MW: 1526.736
• Purity: >98% (HPLC)
• Formula: C₅₉H₇₉N₁₅O₂₁S₆
• SMILES: CC1C(=O)NC2CSSCC3C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(NC(=O)CNC(=O)C(NC2=O)C(C)O)C(=O)NC(CC4=CC=C(C=C4)O)C(=O)O)C(=O)NC(CSSCC(C(=O)N3)N)C(=O)NC(C(=O)N5CCCC5C(=O)N1)CC(=O)N)CC6=CC=C(C=C6)O)CCC(=O)O
• Target: Guanylate Cyclase
• Solubility: 10 mM in DMSO

Bioactivity

• In Vivo:
  Pharmacokinetic analysis shows very low oral bioavailability (0.10%). In intestinal secretion and transit models, linaclotide exhibits significant pharmacological effects in wt, but not in GC-C null mice: induction of increased fluid secretion into surgically ligated jejunal loops is accompanied by the secretion of elevated levels of cyclic guanosine-3', 5-monophosphate and accelerated gastrointestinal transit. Linaclotide significantly increases weekly spontaneous bowel movements and complete spontaneous bowel movements (CSBMs) while reducing abdominal pain in patients with chronic constipation.
• In Vitro:
  Linaclotide inhibits in vitro [125I]-STa binding to intestinal mucosal membranes from wt mice in a concentration-dependent manner. In contrast, [125I]-STa binding to these membranes from GC-C null mice is significantly decreased. After incubation in vitro in jejunal fluid for 30 min, linaclotide is completely degraded. Linaclotide acts on guanylate cyclase-C receptors on the luminal membrane to increase chloride and bicarbonate secretions into the intestine and inhibit the absorption of sodium ions, thus increasing the secretion of water into the lumen and improving defecation; the drug is minimally absorbed into the systemic circulation.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Quick Database Links

Gene Symbol

Guanylate Cyclase