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The SARfaris: GPCR, Kinase, ADME

Sunday, 6 January 2013

New Drug Approvals 2012 - Pt. XXIX - Pasireotide diaspartate (SIGNIFOR®)

ATC code: H01CB05
Wikipedia: Pasreotide

On December 14, the FDA approved Pasireotide diaspartate (SIGNIFOR®, Research CodeL SOM-230, CAS# 396091-73-9, Pub-Chem : CID 9941444, KEGG : D10147), a cyclohexide with pharmacologic properties mimicking those of natural hormone Somatostatin for treatment of adult patients with Cushing's disease (CD) for whom pituitary surgery is not an option or has not been curative.

Cushing's disease (CD) is a cause of Cushing's syndrome characterised by increased secretion of ACTH (adrenocorticotropic hormone) from the anterior pituitary. CD is a rare hormone disorder, and  recent statistics indicate that the annual incidence is somewhere between 1 and 10 per million and is 3 times more common in women than in men (from NEMDIS). This is most often as a result of pituitary adenoma or due to excess production of hypothalamus Corticotropin releasing hormone (CRH). More information can be found in Medscape.

The therapeutic activity of Pasireotide diaspartate is through binding to Somatostatin receptors (SSTRs). They belong to GPCR class of targets and there are five known SSTRs in human: SSTR1 (CHEMBL1917P30872), SSTR2 (CHEMBL1804P30874), SSTR3 (CHEMBL2028P32745), SSTR4 (CHEMBL1853P31391) and SSTR5 (CHEMBL1792P35346). These receptor subtypes are expressed in different tissues under normal physiological condition. Corticotroph tumor cells from CD patients frequently over express SSTR5, whereas the other receptor subtypes are often not expressed or expressed at lower levels. Pasireotide diaspartate has a 40-fold increased affinity to SSTR5 than other SSTR analogs binds and activates the receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

Since the targets of this drug belong to same family of receptors (somatostatin receptors), multiple  sequence alignment of human SSTR1, 2, 3, 4 and 5 receptors was done using T-coffee which is shown above. The protein sequences (fasta format) of human SSTR1, 2, 3, 4 and 5 can be downloaded from this link here. (courtesy UniProt)

Standard InChI : 1/C58H66N10O9/c59-27-13-12-22-46-52(69)64-47(30-38-23-25-42(26-24-38)76-36-39-16-6-2-7-17-39)53(70)66-49(31-37-14-4-1-5-15-37)57(74)68-35-43(77-58(75)61-29-28-60)33-50(68)55(72)67-51(40-18-8-3-9-19-40)56(73)65-48(54(71)63-46)32-41-34-62-45-21-11-10-20-44(41)45/h1-11,14-21,23-26,34,43,46-51,62H,12-13,22,27-33,35-36,59-60H2,(H,61,75)(H,63,71)(H,64,69)(H,65,73)(H,66,70)(H,67,72)/t43-,46+,47+,48-,49+,50+,51+/m1/s1/f/h61,63-67H

Smiles : NCCCC[C@H]1C(N[C@H](C(N[C@H](C(N2[C@H](C(N[C@H](C(N[C@@H](C(N1)=O)CC1=CNC3=CC=CC=C13)=O)C1=CC=CC=C1)=O)C[C@H](C2)OC(NCCN)=O)=O)CC2=CC=CC=C2)=O)CC2=CC=C(C=C2)OCC2=CC=CC=C2)=O
Iupac Name : (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt

Pasireotide diaspartate is a Somatostatin analog and is cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. The recommended dosage range of Pasireotide diaspartate is 0.3 to 0.9 mg administered as subcutaneous injection twice a day.

Pasireotide diaspartate demonstrates approximately linear pharmacokinetics for a dose range from 0.0025 to 1.5 mg in healthy patients with dose proportional Cmax and AUC and Tmax of 0.25 to 0.5 hrs. Apparent volume of distribution (Vz/F) was >100 L with plasma concentration of about 91%. Plasma protein binding was moderate (88%). It is shown to be metabolically stable in human liver and kidney and is eliminated mainly via hepatic clearance.

Full prescribing information can be found here.

The license holder is Novartis Pharmaceuticals, and the product website is

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