Linaclotide

Các tên gọi khác (3) :

Cys cys glu tyr cys cys asn pro ala cys thr gly cys tyr (disulfide bridge: 1-6; 2-10; 5-13)
L-Cysteinyl-L-cysteinyl-L-alpha-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclic (1->6),(2->10),(5->13)-tris(disulfide)
Linzess

Thuốc Gốc

Small Molecule

CAS: 851199-59-2

ATC: A06AX04

CTHH: C₅₉H₇₉N₁₅O₂₁S₆

PTK: 1526.736

Linaclotide is an orally administered, peptide agonist of guanylate cyclase 2C for the treatment of irritable bowel syndrome. Chemically, it is a heterodetic cyclic peptide and consists of fourteen amino acids. The protein sequence is as follows: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr. There are three disulfide bonds which are located between Cys1 and Cys6; between Cys2 and Cys10; and between Cys5 and Cys13. FDA approved on August 30, 2012.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₅₉H₇₉N₁₅O₂₁S₆

Phân tử khối

1526.736

Monoisotopic mass

1525.389918805

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

InChI Key

InChIKey=KXGCNMMJRFDFNR-WDRJZQOASA-N

IUPAC Name

(2S)-2-{[(1R,4S,7S,13S,16R,21R,24R,27S,30S,33R,38R,44S)-21-amino-13-(carbamoylmethyl)-27-(2-carboxyethyl)-44-[(1R)-1-hydroxyethyl]-30-[(4-hydroxyphenyl)methyl]-4-methyl-3,6,12,15,22,25,28,31,40,43,46,51-dodecaoxo-18,19,35,36,48,49-hexathia-2,5,11,14,23,26,29,32,39,42,45,52-dodecaazatetracyclo[22.22.4.2¹⁶,³³.0⁷,¹¹]dopentacontan-38-yl]formamido}-3-(4-hydroxyphenyl)propanoic acid

Traditional IUPAC Name

SMILES

[H][C@]1(CSSC[C@]2([H])NC(=O)[C@H](CC3=CC=C(O)C=C3)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]3CSSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSSC[C@H](N)C(=O)N3)NC2=O)C(=O)N[C@@]([H])([C@@H](C)O)C(=O)NCC(=O)N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O

Độ hòa tan

Slightly soluble

logP

-11

logS

-3.3

pKa (strongest acidic)

3.06

pKa (Strongest Basic)

7.65

PSA

573.91 Å²

Refractivity

368 m³·mol^-1

Polarizability

145.88 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

-1

Number of Rings

Bioavailability

MDDR-Like Rule

true

Dược Lực Học : Changes in the appearance and consistency of stools as measured by the Bristol Stool Form Scale (BSFS) have been noted after taking linaclotide.

Cơ Chế Tác Dụng : Linaclotide is an orally administered, peptide agonist of guanylate cyclase 2C for the treatment of irritable bowel syndrome. Chemically, it is a heterodetic cyclic peptide and consists of fourteen amino acids. The protein sequence is as follows: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr. There are three disulfide bonds which are located between Cys1 and Cys6; between Cys2 and Cys10; and between Cys5 and Cys13. FDA approved on August 30, 2012. Linaclotide is an agonist of guanylate cyclase-C (GC-C). Once linaclotide and its active metabolite binds to GC-C, it has local effect on the luminal surface of the intestinal epithelium. Activation of GC-C by linaclotide results in the intra- and extracellular increase of cyclic guanosine monophosphate concentrations (cGMP). This elevation of cGMP levels stimulates the secretion of chloride and bicarbonate into the intestinal lumen via activation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Ultimately, linaclotide helps patients with IBS (especially with constipation) as GI transit is accelerated and the release of intestinal fluid is increased. In animal models, a decrease in visceral pain after administration of linaclotide may be observed. A decrease in the activity of pain-sensing nerves occurs as a result of an increase in extracellular cGMP.

Dược Động Học :

▧ Absorption :
When taken orally, linaclotide is not absorbed into the systemic. No detectable levels of linaclotide or its active metabolite were noted after doses of 125 mcg or 290 mcg were administered.
▧ Volume of Distribution :
Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.
▧ Metabolism :
Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite, MM-419447, by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.
▧ Route of Elimination :
Linaclotide is eliminated fecally (3 - 5% as active metabolites). However most of the dose undergoes proteolysis (processes include reduction of disulfide bonds) in the intestine before being excreted via feces.
▧ Half Life :
Because linaclotide is not systemically absorbed, half life cannot be calculated.

Độc Tính : Most common adverse reactions (incidence of at least 2%) reported in IBS-C or CIC patients are diarrhea, abdominal pain, flatulence and abdominal distension.

Chỉ Định : Treatment of irritable bowel syndrome (IBS) with constipation and chronic idiopathic constipation.

Liều Lượng & Cách Dùng : Capsule - Oral - 145 mcg, 290 mcg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Forest Pharmaceuticals, Inc.

Sản phẩm biệt dược : Linzess

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB08890

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09355

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0456-1202-30

Wikipedia

http://en.wikipedia.org/wiki/Linaclotide

RxList

http://www.rxlist.com/linzess-drug.htm

Drugs.com

http://www.drugs.com/cdi/linaclotide.html

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