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New Drug Approvals 2012 - Pt. XVII - Linaclotide (LinzessTM)



ATC Code: A03A (incomplete)
Wikipedia: Linaclotide

On Agust 30, the FDA approved Linaclotide (tradename: Linzess; Research Code: MD-1100, ASP-0456), a novel, first-in-class Guanylate Cyclase-C (GC-C) agonist indicated for the treatment in adults of irritable bowel syndrome with constipation (IBS-C), and chronic idiophatic constipation (CIC). CIC is a diagnosis given to people who experience persistent constipation and do not respond to standard treatment. IBS-C is a subtype characterized by chronic abnominal pain, discomfort, bloating and alteration of bowel habits. Linaclotide exherts its therapeutic action by binding to GC-C, resulting in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Increase in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. Linaclotide has been shown, in animal models, to not only accelerate gastrointestinal (GI) transit, but also to reduce intestinal pain, which is thought to be mediated by increased extracellular cGMP.

Other treatments for IBS have been already in the market and these include treatments with antimuscarinic drugs, such as Dicyclomine (approved in 1950; tradename: Bentyl; ChEMBL: CHEMBL1123), Methantheline (approved in 1951, tradename: Banthine; ChEMBL: CHEMBL1201264), a serotonin agonist, such as Tegaserod (approved in 2002; tradename: Zelnorm; ChEMBL: CHEMBL1201332) and a serotonin antagonist, such as Alosetron (approved in 2000; tradename: Lotronex; Chembl: CHEMBL1110) and Lubiprostone (approved in 2006; tradename: Amitiza; ChEMBL: CHEMBL1201134), a chloride channel activator. While these drugs act by either inhibiting the muscarinic action of acethylcholine, or through the activation of the serotonin receptors of the nervous system in the GI tract, or by activating the chloride channels on the GI epithelial cells, Linaclotide represents the first GC-C agonist to ever reach the market.

GC-C (ChEMBL: CHEMBL1795197; Uniprot: P25092) is a 1073 amino-acid long enzyme, which has an extracellular ligand binding domain (PFAM: ANF_receptor), a domain similar to that of protein tyrosine kinases (PFAM: Pkinase_Tyr) and a adenylate and guanylate cyclase catalytic domain (PFAM: Guanylate_cyc).

>GUC2C_HUMAN Heat-stable enterotoxin receptor
MKTLLLDLALWSLLFQPGWLSFSSQVSQNCHNGSYEISVLMMGNSAFAEPLKNLEDAVNE
GLEIVRGRLQNAGLNVTVNATFMYSDGLIHNSGDCRSSTCEGLDLLRKISNAQRMGCVLI
GPSCTYSTFQMYLDTELSYPMISAGSFGLSCDYKETLTRLMSPARKLMYFLVNFWKTNDL
PFKTYSWSTSYVYKNGTETEDCFWYLNALEASVSYFSHELGFKVVLRQDKEFQDILMDHN
RKSNVIIMCGGPEFLYKLKGDRAVAEDIVIILVDLFNDQYFEDNVTAPDYMKNVLVLTLS
PGNSLLNSSFSRNLSPTKRDFALAYLNGILLFGHMLKIFLENGENITTPKFAHAFRNLTF
EGYDGPVTLDDWGDVDSTMVLLYTSVDTKKYKVLLTYDTHVNKTYPVDMSPTFTWKNSKL
PNDITGRGPQILMIAVFTLTGAVVLLLLVALLMLRKYRKDYELRQKKWSHIPPENIFPLE
TNETNHVSLKIDDDKRRDTIQRLRQCKYDKKRVILKDLKHNDGNFTEKQKIELNKLLQID
YYNLTKFYGTVKLDTMIFGVIEYCERGSLREVLNDTISYPDGTFMDWEFKISVLYDIAKG
MSYLHSSKTEVHGRLKSTNCVVDSRMVVKITDFGCNSILPPKKDLWTAPEHLRQANISQK
GDVYSYGIIAQEIILRKETFYTLSCRDRNEKIFRVENSNGMKPFRPDLFLETAEEKELEV
YLLVKNCWEEDPEKRPDFKKIETTLAKIFGLFHDQKNESYMDTLIRRLQLYSRNLEHLVE
ERTQLYKAERDRADRLNFMLLPRLVVKSLKEKGFVEPELYEEVTIYFSDIVGFTTICKYS
TPMEVVDMLNDIYKSFDHIVDHHDVYKVETIGDAYMVASGLPKRNGNRHAIDIAKMALEI
LSFMGTFELEHLPGLPIWIRIGVHSGPCAAGVVGIKMPRYCLFGDTVNTASRMESTGLPL
RIHVSGSTIAILKRTECQFLYEVRGETYLKGRGNETTYWLTGMKDQKFNLPTPPTVENQQ
RLQAEFSDMIANSLQKRQAAGIRSQKPRRVASYKKGTLEYLQLNTTDKESTYF


Linaclotide is an oral peptide drug, comprised of 14 amino acids and with disulfide bonds between cysteines (1-6), (2-10) and (3-15). Linaclotide has a molecular weight of 1526.8 Da. (Name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L­-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5­-13)-tris (disulfide); CanonicalSmiles: C[C@@H](O)[C@@H]1NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@@H](N)CSSC[C@H](NC(=O)[C@H](CSSC[C@H](NC(=O)CNC1=O)C(=O)N[C@@H](Cc4ccc(O)cc4)C(=O)O)NC(=O)[C@H](Cc5ccc(O)cc5)NC(=O)[C@H](CCC(=O)O)NC3=O)C(=O)N[C@@H](CC(=O)N)C(=O)N6CCC[C@H]6C(=O)N[C@@H](C)C(=O)N2; InChI: InChI=1S/C59H79N15O21S6/c1-26-47(82)69-41-25-101-99-22-38-52(87)65-33(13-14-45(80)81)49(84)66-34(16-28-5-9-30(76)10-6-28)50(85)71-40(54(89)72-39(23-97-96-20-32(60)48(83)70-38)53(88)67-35(18-43(61)78)58(93)74-15-3-4-42(74)56(91)63-26)24-100-98-21-37(64-44(79)19-62-57(92)46(27(2)75)73-55(41)90)51(86)68-36(59(94)95)17-29-7-11-31(77)12-8-29/h5-12,26-27,32-42,46,75-77H,3-4,13-25,60H2,1-2H3,(H2,61,78)(H,62,92)(H,63,91)(H,64,79)(H,65,87)(H,66,84)(H,67,88)(H,68,86)(H,69,82)(H,70,83)(H,71,85)(H,72,89)(H,73,90)(H,80,81)(H,94,95)/t26-,27+,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1)

The recommended dosage of Linaclotide is 290 mcg orally once daily for the case of IBS-C, and 145 mcg orally once daily for the treatment of CIC, on empty stomach at least 30 minutes prior to first meal of the day.

Linaclotide is minimally absorbed with low systemic availability following oral administration. Concentrations of Linaclotide and its active metabolite in plasma are below quantitation after oral doses of 145 mcg and 290 mcg were administrated. Therefore Linaclotide is expected to be minimally distributed to tissues. Linaclotide is metabolised within the GI tract to its active metabolite by loss of the terminal tyrosine moiety. Both Linaclotide and the metabolite are proteolitically degraded within the intestinal lumen to smaller peptides and naturally occuring amino acids. Following the daily administration of 290 mcg of Linaclotide for seven days, about 5% and 3% were recovered in the feces of fasted and fed subjects, respectively, and virtually all as the active metabolite.

The license holder is Ironwood Pharmaceuticals, Inc. and the full prescribing information of Linaclotide can be found here.

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