Degarelix

gonadotropin releasing hormone antagonist

Thuốc Gốc

Small Molecule

CAS: 214766-78-6

ATC: L02BX02

CTHH: C₈₂H₁₀₃ClN₁₈O₁₆

PTK: 1632.259

Degarelix is used for the treatment of advanced prostate cancer. Degarelix is a synthetic peptide derivative drug which binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocks interaction with GnRH. This antagonism reduces luteinising hormone (LH) and follicle-stimulating hormone (FSH) which ultimately causes testosterone suppression. Reduction in testosterone is important in treating men with advanced prostate cancer. Chemically, it is a synthetic linear decapeptide amide with seven unnatural amino acids, five of which are D-amino acids. FDA approved on December 24, 2008.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₈₂H₁₀₃ClN₁₈O₁₆

Phân tử khối

1632.259

Monoisotopic mass

1630.748797045

InChI

InChI=1S/C82H103ClN18O16/c1-45(2)35-60(72(107)92-59(16-9-10-33-87-46(3)4)80(115)101-34-12-17-68(101)79(114)88-47(5)70(84)105)93-74(109)63(38-51-23-30-58(31-24-51)91-81(85)116)95-76(111)64(39-50-21-28-57(29-22-50)90-71(106)66-42-69(104)100-82(117)99-66)97-78(113)67(44-102)98-77(112)65(41-53-13-11-32-86-43-53)96-75(110)62(37-49-19-26-56(83)27-20-49)94-73(108)61(89-48(6)103)40-52-18-25-54-14-7-8-15-55(54)36-52/h7-8,11,13-15,18-32,36,43,45-47,59-68,87,102H,9-10,12,16-17,33-35,37-42,44H2,1-6H3,(H2,84,105)(H,88,114)(H,89,103)(H,90,106)(H,92,107)(H,93,109)(H,94,108)(H,95,111)(H,96,110)(H,97,113)(H,98,112)(H3,85,91,116)(H2,99,100,104,117)/t47-,59+,60+,61-,62-,63-,64+,65-,66-,67+,68?/m1/s1

InChI Key

InChIKey=MEUCPCLKGZSHTA-RHCWOGDZSA-N

IUPAC Name

(4R)-N-{4-[(2S)-2-{[(1R)-2-[4-(carbamoylamino)phenyl]-1-{[(1S)-1-{[(2S)-1-(2-{[(1R)-1-carbamoylethyl]carbamoyl}pyrrolidin-1-yl)-1-oxo-6-[(propan-2-yl)amino]hexan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}ethyl]carbamoyl}-2-[(2S)-2-[(2R)-2-[(2R)-3-(4-chlorophenyl)-2-[(2R)-2-acetamido-3-(naphthalen-2-yl)propanamido]propanamido]-3-(pyridin-3-yl)propanamido]-3-hydroxypropanamido]ethyl]phenyl}-2,6-dioxo-1,3-diazinane-4-carboxamide

Traditional IUPAC Name

(4R)-N-{4-[(2S)-2-{[(1R)-2-[4-(carbamoylamino)phenyl]-1-{[(1S)-1-{[(2S)-1-(2-{[(1R)-1-carbamoylethyl]carbamoyl}pyrrolidin-1-yl)-6-(isopropylamino)-1-oxohexan-2-yl]carbamoyl}-3-methylbutyl]carbamoyl}ethyl]carbamoyl}-2-[(2S)-2-[(2R)-2-[(2R)-3-(4-chlorophenyl)-2-[(2R)-2-acetamido-3-(naphthalen-2-yl)propanamido]propanamido]-3-(pyridin-3-yl)propanamido]-3-hydroxypropanamido]ethyl]phenyl}-2,6-dioxo-1,3-diazinane-4-carboxamide

SMILES

CC(C)C[C@H](NC(=O)[C@@H](CC1=CC=C(NC(N)=O)C=C1)NC(=O)[C@H](CC1=CC=C(NC(=O)[C@H]2CC(=O)NC(=O)N2)C=C1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC1=CN=CC=C1)NC(=O)[C@@H](CC1=CC=C(Cl)C=C1)NC(=O)[C@@H](CC1=CC2=CC=CC=C2C=C1)NC(C)=O)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1CCCC1C(=O)N[C@H](C)C(N)=O

Độ hòa tan

4.10e-03 g/l

logP

-1.4

logS

-5.6

pKa (strongest acidic)

10.49

pKa (Strongest Basic)

11.02

PSA

512.87 Å²

Refractivity

431.13 m³·mol^-1

Polarizability

169.03 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

MDDR-Like Rule

true

Dược Lực Học : Degarelix is a synthetic derivative of GnRH decapeptide, the ligand of the GnRH receptor. Gonadotropin and androgen production result from the binding of endogenous GnRH to the GnRH receptor. Degarelix antagonizes the GnRH receptor which in turn blocks the release of LH and FSH from the pituitary. LF and FSH decreases in a concentration-dependent manner. The reduction in LH leads to a decrease in testosterone release from the testes.

Cơ Chế Tác Dụng : Degarelix is used for the treatment of advanced prostate cancer. Degarelix is a synthetic peptide derivative drug which binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland and blocks interaction with GnRH. This antagonism reduces luteinising hormone (LH) and follicle-stimulating hormone (FSH) which ultimately causes testosterone suppression. Reduction in testosterone is important in treating men with advanced prostate cancer. Chemically, it is a synthetic linear decapeptide amide with seven unnatural amino acids, five of which are D-amino acids. FDA approved on December 24, 2008. GnRH antagonists compete with natural GnRH for binding to GnRH receptors in the pituitary gland. This reversible blinding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the testes and subsequently reduces the size and growth of the prostate cancer.

Dược Động Học :

▧ Absorption :
Degarelix forms a depot at the site of injection after subcutaneous administration from which the drug slowly released into circulation. After a single bolus dose of 2mg/kg, peak plasma concentrations of degarelix occured within 6 hours at a concentration of 330 ng/mL. Ki = 0.082 ng/mL and 93% of receptors were fully suppressed; MRT = 4.5 days.
▧ Volume of Distribution :
Central compartment: 8.88 - 11.4 L; Peripheral compartment: 40.9 L
▧ Protein binding :
90% of the drug is bound to plasma proteins.
▧ Metabolism :
70% - 80% of degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and then fecally eliminated. No active or inactive metabolites or involvement of CYP450 isozymes.
▧ Route of Elimination :
Fecal (70% to 80%) and renal (20%-30% of unchanged drug)
▧ Half Life :
Terminal half-life: 41.5 - 70.2 days; Absorption half-life: 32.9 hours; Half-life from injection site: 1.17 days.
▧ Clearance :
Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.

Độc Tính : The most commonly observed adverse reactions (> 10%) during degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT).

Chỉ Định : Degaralix is used for the management of advanced prostate cancer.

Tương Tác Thuốc :

Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Mifepristone Enhance QTc-prolonging effect

Liều Lượng & Cách Dùng : Injection, powder, for solution - Subcutaneous - 80 mg, 120 mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Ferring Pharmaceuticals Inc.

Sản phẩm biệt dược : Firmagon

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB06699

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=44151801

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=99443253

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D08901

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/55566-8401-0

PharmGKB

http://www.pharmgkb.org/drug/PA165958373

Wikipedia

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

RxList

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

Drugs.com

http://www.drugs.com/degarelix.html

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