396091-73-9 Usage
Description
Pasireotide, also known as SOM230, is a cyclohexapeptide somatostatin analogue designed to inhibit the release of adrenocorticotropic hormone (ACTH). It was developed to have long-lasting inhibitory effects and is used in the treatment of Cushing's Disease (CD) in adult patients who have not responded to surgical intervention or for whom surgery is not an option. Pasireotide works by binding to somatostatin receptors (SSTRs), which play a crucial role in regulating endocrine and exocrine release in various tissues.
Uses
Used in Pharmaceutical Industry:
Pasireotide is used as a therapeutic agent for the treatment of Cushing's Disease (CD) in adult patients who have not responded to surgical intervention or for whom surgery is not an option. It helps in managing the symptoms and complications associated with CD by inhibiting the release of ACTH, which in turn reduces the production of cortisol.
Used in Biological Studies:
Pasireotide is also used in the biological study of long-term treatment of Cushing's Disease, with 5-year results from an open-label extension study of a Phase III trial. This helps researchers understand the long-term effects and efficacy of pasireotide in managing CD and its potential impact on patient outcomes.
Brand Name:
The brand name for pasireotide is Signifor.
Originator
Novartis (Switzerland)
Clinical Use
Pasireotide, also known as SOM230, is a cyclic, hexameric peptide developed by Novartis which
exhibits somatostatin-like activity as an antisecretory agent used in the treatment of Cushing’s
disease. Pasireotide activates a broad range of somatostatin receptors, and in particular displays a
significantly higher binding affinity for somatostatin receptors 1, 3, and 5 than its competitor
somatostatin-mimic octreotide in vitro, as well as a comparable binding affinity for somatostatin
receptor 2. Pasireotide is more potent than somatostatin in inhibiting the secretion of human growth
hormone (HGH), glucagon, and insulin.
Synthesis
The synthesis of pasireotide is relatively straightforward, given that the chemical entity is a cyclic
peptide. The most likely scalable route closely mimics that described by the discovery authors
involving a series of conventional couplings and deprotection steps to arrive at a linear peptide which
then underwent sequential release from solid support, macrocyclization, and a global deprotection step.Beginning from (2S,4R)-4-hydroxyproline methyl ester (110) in the scheme above, this pyrrolidine
nitrogen was first Fmoc-protected in 85% yield followed by treatment with trisphosgene and N-Boc
diaminoethane to provide the prolino carbamate shown in 49% yield over the two step sequence after a
recrystallization with ethyl acetate.Next, commercially available Fmoc-Tyr(Bzl)-O-CH2-Ph(3-OCH3)-O-CH2-SASRIN157 resin (112)
was used as starting material in a manually operated reactor and carried through a standard protocol
consisting of repetitive cycles of Nα deprotection (piperidine/DMF, 2:8), repeated washings with DMF,
and coupling using DIC/HOBT in DMF (Schemes 2 and 3). The following amino acid derivatives
were sequentially coupled: Fmoc-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-PhG-OH, proline
derivative 111 above, and finally Fmoc-Phe-OH. Couplings were continued or repeated until complete
disappearance of residual amino groups as monitored with a ninhydrin stain test. Before cleavage of the
protected linear peptide from its resin support, the Fmoc group was removed. After washings with
dichloromethane, the peptide resin was transferred into a column and the peptide fragment was cleaved
from solid support upon subjection to 2% TFA in dichloromethane. The eluate was immediately
neutralized with a saturated NaHCO3 solution which resulted in the side chain protected fragment 119
(the Scheme) was obtained in 93% homogeneity and cyclized without further purification. For
cyclization, the linear fragment was dissolved in DMF, treated with DIPEA, and then 1.5 equiv of
diphenylphosphoryl azide which resulted in the protected cyclized product obtained in good yield. For complete deprotection, the residue was dissolved at 0 °C in aqueous TFA, and the mixture was stirred at
this temperature for 30 min. The product was then precipitated with ether containing ca. 10 equiv of
HCl, then filtered and washed with ether, and finally dried. The entire sequence produced pasireotide
(XVIII) in 20% yield from resin-bound 112.
Drug interactions
Potentially hazardous interactions with other drugs
Antifungals: avoid with ketoconazole.
Ciclosporin: possibly reduces ciclosporin
concentration.
Metabolism
Pasireotide is metabolically highly stable and in vitro
data show that pasireotide is not a substrate, inhibitor
or inducer of any major enzymes of CYP450. In healthy
volunteers, pasireotide is mainly found in the unchanged
form in plasma, urine and faeces.
Pasireotide is eliminated mainly by hepatic clearance
and is mostly found, unchanged, in the faeces (48%) and
urine.
Check Digit Verification of cas no
The CAS Registry Mumber 396091-73-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 3,9,6,0,9 and 1 respectively; the second part has 2 digits, 7 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 396091-73:
(8*3)+(7*9)+(6*6)+(5*0)+(4*9)+(3*1)+(2*7)+(1*3)=179
179 % 10 = 9
So 396091-73-9 is a valid CAS Registry Number.
396091-73-9Relevant articles and documents
NOVEL PROCESS FOR THE PREPARATION OF PASIREOTIDE
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Page/Page column 20, (2017/01/09)
The present invention relates to a novel process for the preparation of Pasireotide of formula 11 [Cyclo [Phe-{4-(OCO-NH-CH2-CH2-NH2)) Pro}-Phg-DTrp-Lys-Tyr(Bzl)]]. The invention also relates to a novel intermediate compound of formula 8 and process thereof which is used for preparation of compound of formula 11.
