New Drug Approvals 2013 - Pt. XVII - Flutemetamol F18 (VizamylTM)

ATC Code: V09AX04

On October 25^th, the FDA approved Flutemetamol F18 (Tradename: Vizamyl; Research Code: [¹⁸F]AH110690 ), a radioactive diagnostic agent, for intravenous (i.v.) use in Positron Emission Tomography (PET) imaging of the brain in adult patients with cognitive impairment, who are being evaluated for Alzheimer’s disease (AD) and dementia.

Alzheimer's disease is a non-treatable, progressively worsening and fatal disease, characterised by a decrease in cognitive functions, such as memory, and is usually associated with an accumulation of β amyloid (Uniprot: P05067) plaques in several brain regions. These deposits are believed to be responsible for cellular damage and ultimately cell death.

Flutemetamol F18 is the second approved diagnostic drug to estimate β-amyloid neuritic plaque density, after the approval of Florbetapir F18 in 2012. Like Florbetapir F18, Flutemetamol F18 binds to β amyloid plaques in the brain where the F-18 isotope produces a positron signal that can be detected by a PET scanner. The advantages of this compound over its predecessor are: exposure to a lower dose of radiation; and more time for PET image acquisition (20 vs. 10 minutes). In in vitro binding studies using postmortem human brain homogenates containing fibrillar β amyloid, the dissociation constant (Kd) for flutemetamol was 6.7 nM.

It is worth mentioning, that a positive scan, indicating the presence of β amyloid deposits, it's not enough to diagnose a patient with Alzheimer's disease, since these protein deposits can also be present in patients with other types of dementia, or in elderly people without any neurological disease. However, a negative scan, where little or none β-amyloid plaques can be detected, indicates that the cause for dementia is probably not due to Alzheimer's disease.

Flutemetamol F18 (IUPAC Name: 2-[3-fluoranyl-4-(methylamino)phenyl]-1,3-benzothiazol-6-ol; Canonical smiles: CNc1ccc(cc1[18F])c2nc3ccc(O)cc3s2 ; ChEMBL: CHEMBL2042122; PubChem: 15950376; ChemSpider: 13092196; Standard InChI Key: VVECGOCJFKTUAX-HUYCHCPVSA-N) is a synthetic small molecule with a radioactive isotope of fluorine (¹⁸F), with a molecular weight of 274.3 Da, 3 hydrogen bond acceptors, 2 hydrogen bond donors, and has an ALogP of 3.61. The compound is therefore fully compliant with the rule of five.

Flutemetamol F18 is available as a radioactive solution for intravenous injection and the recommended imaging dose is 185 megabecquerels (MBq) [5 millicuries(mCi)] in a total volume of 10 mL or less. Following intravenous injection, the plasma concentrations declines by approximately 75% in the first 20 minutes post-injection, and by approximately 90% in the first 180 minutes. Flutemetamol F18 metabolites are primarily excreted via the hepatobiliary (52%) and the renal system (37%).

The license holder for Vizamyl^TM is GE Healthcare, and the full prescribing information can be found here.

New Drug Approvals 2013 - Pt. XVII - Macitentan (Opsumit ®)

ATC Code: C02KX (imcomplete)

Wikipedia: Macitentan

ChEMBL: CHEMBL2103873

On October 13th the FDA approved Macitentan (trade name Opsumit ®) for the treatment of pulmonary arterial hypertension (PAH). Macitentan is an endothelin receptor antagonist (with affinities to both Endothelin ET-A (ETA) and Endothelin ET-B (ETB) receptor subtypes, similar in mechanism of action to the previously licensed drug Bosentan, CHEMBLID957).

Target(s)

The Endothelin receptor ET-A (ETA, CHEMBLID252 ; Uniprot P25101) and Endothelin receptor ET-B (ETB, CHEMBLID1785 ; Uniprot P24530) receptors mediate a number of physiological effects via the natural peptide agonist Endothelin-1 (ET1 , CHEMBL437472 ; Uniprot P05305). In addition to normal roles in supporting homeostasis, these effects can include pathologies such as inflammation, vasoconstriction, fibrosis and hypertrophy.



Macitentan acts as an antagonist for both receptors with both a high affinity and long residence time in human pulmonary arterial smooth muscle cells. Hence it counteracts vasoconstriction and relieves hypertension. One of the metabolites of Macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro

Macitentan (CHEMBL2103873 ; Pubchem : 16004692 ) is a small molecule drug with a molecular weight of 588.3 Da, an AlogP of 3.67, 11 rotatable bonds, and 1 rule of 5 violation.

Canonical SMILES : CCCNS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1c3ccc(Br)cc3

InChi: InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)

Dosage

10 mg once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.



Metabolism and Elimination 

Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with a minor contribution of CYP2C19. It is interesting to note the presence of bromine atoms in two of the aryl rings, typically a lighter halogen, typically fluorine is used to block oxidative P450-mediated metabolism at these exposed aromatic positions.



At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces.



Pregnancy

Macitentan may cause fetal harm when administered to a pregnant woman. Macitentan is contraindicated in females who are pregnant.



Hepatotoxicity

Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. Obtain liver enzyme tests prior to initiation of Macitentan and repeat during treatment as clinically indicated.



Hemoglobin Decrease 

Decreases in hemoglobin concentration and hematocrit have occurred following administration

of other ERAs and were observed in clinical studies with Macitentan. These decreases occurred

early and stabilized thereafter Initiation of Macitentan is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.



Strong CYP3A4 Inducers / Inhibitors

Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure whereas concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir (CHEMBL163) are strong inhibitors of CYP3A4.

The license holder is Actelion Pharmaceuticals US the full prescribing information can be found here.

New Drug Approvals 2013 - Pt. XVI - Riociguat (AdempasTM)

ATC code: not yet assigned

Wikipedia: Riociguat

On October 8, 2013, the FDA approved riociguat for the treatment of
patients suffering from two forms of pulmonary hypertension - chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary arterial hypertension (PAH).



Pulmonary hypertension (PH) is a disease characterized by abnormally high blood pressure in the lungs, which increases the workload for the right ventricle of the heart. Some of the symptoms of PH are dizziness, shortness of breath and water deposits in the legs and joints. PH progresses slowly and can lead to severe and often fatal circulatory and respiratory complications. CTEPH is a form of PH caused by blood clots obstructing the passage of blood through the vessels in the lung, often after a pulmonary embolism has occurred. PAH on the other hand is caused by a chronic tightening or constriction of blood vessels.



Riociguat (CHEMBL2107834) is a stimulator of soluble guanylate cyclase (sGC), an ezyme that is activated by increased levels of nitric oxide (NO). Downstream signalling of increased levels of cGMP (CHEBI:28181) causes the dilation of the endothelium in blood vessels. SGc is a heterodimer consisting of an alpha- and beta-subunit. There are two known isoforms for each subunit (Uniprot-ids, alpha: P33402, Q02108 ; beta: Q02153, O75343). Stimulation of the kinase by riociguat and other sGC stimulators depends on the presence of a reduced heme group in the sGC beta-subunit. The activation of sGC by this class of compounds is synergistic with NO signalling. Some other compounds in this class are YC-1 (CHEMBL333985) and BAY 41-8543 (CHEMBL1916024). In contrast, the sGC can also be targeted through activators that work independently of NO signalling. 

Canonical SMILES: COC(=O)N(C)c1c(N)nc(nc1N)c2nn(Cc3ccccc3F)c4ncccc24

Std-InChI:  InChI=1S/C20H19FN8O2/c1-28(20(30)31-2)15-16(22)25-18(26-17(15)23)14-12-7-5-9-24-19(12)29(27-14)10-11-6-3-4-8-13(11)21/h3-9H,10H2,1-2H3,(H4,22,23,25,26)

Std-InChI key: WXXSNCNJFUAIDG-UHFFFAOYSA-N



Riociguat has a molecular weight of 422.42 Da. The calculated LogP for riociguat is 2.34 and the compound has no stereo-centers.



The compound is administered orally and was approved through the FDA priorities review program. It has a black box warning because it can harm fetuses and is therefore not prescribed to pregnant women. Other adverse effects of riociguat include headache, dizziness, indigestion, peripheral edema, nausea, diarrhea and vomiting.



Riociguat is a first-in-class compound and was developed by Bayer HealthCare Pharmaceuticals.



Riociguat will be marketed as a prescription medicine under the name Adempas.

New Drug Approvals 2013 - Pt. XV - Vortioxetine Hydrobromide (BrintellixTM)

ATC Code: N06AX26

Wikipedia: Vortioxetine

On September 30th 2013, FDA approved Vortioxetine (as the hydrobromide salt; tradename: Britellix; research code: Lu AA21004 (Lu AA21004 (HBR) for the hydrobromide salt); ChEMBL: CHEMBL2104993), a multimodal antidepressant indicated for the treatment of major depressive disorder (MDD).



MDD is a mental disorder characterised by low mood and/or loss of pleasure in most activities, and by symptoms or signs such as increased fatigue, change in appetite or weight, insomnia or excessive sleeping and suicide attempts or thoughts of suicide. MDD is believed to arise from low levels of neurotransmitters (primarily serotonin (5-HT), norepinepherine (NE) and dopamine(DA)) in the synaptic cleft between neurons in the brain. Several antidepressants for the treatment of MDD are already available in the market and its choice depends on which symptoms need to be tackled. The most important classes of antidepressants include the Selective Serotonin Reuptake Inhibitors (SSRIs) such as Fluoxetine (ChEMBL: CHEMBL41), Sertraline (ChEMBL: CHEMBL809), Paroxetine (ChEMBL: CHEMBL490), Fluvoxamine (ChEMBL: CHEMBL814) and Escitalopram (ChEMBL: CHEMBL1508), which are believed to maintain the levels of 5-HT high in the synapse; and the Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) such as Venlafaxine (ChEMBL: CHEMBL637), Duloxetine (ChEMBL: CHEMBL1175), Desvenlafaxine (ChEMBL: CHEMBL1118) and Milnacipran (ChEMBL: CHEMBL259209), which in turn are thought to maintain higher levels of 5-HT and NE in the synapse. Vortioxetine is a novel multimodal serotonergic compound, which displays antagonistic properties at serotonin receptors 5-HT_3A (ChEMBL: CHEMBL1899; K_i=3.7nM) and 5-HT₇ (ChEMBL: CHEMBL3155; K_i=19nM), partial agonist properties at 5-HT_1B receptors (ChEMBL: CHEMBL1898; K_i=33nM), agonistic properties at 5-HT_1A receptors (ChEMBL: CHEMBL214; K_i=15nM) and potent inhibition at the serotonin transporter (SERT) (ChEMBL: CHEMBL228; K_i=1.6nM). The contribution of these activities to the antidepressant action of Vortioxetine is not fully understood, however Vortioxetine is believed to be the first compound with this combination of pharmacodynamic activity.

Vortioxetine is a synthetic small molecule with a molecular weight of 298.5 g.mol^-1 (379.4 g.mol^-1 for the hydrobromide salt), an ALogP of 4.5, 3 hydrogen bond acceptors, 1 hydrogen bond donor, and therefore fully compliant with Lipinski's rule of five.

IUPAC: 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide

Canonical Smiles: Cc1ccc(Sc2ccccc2N3CCNCC3)c(C)c1

InCHI: InChI=1S/C18H22N2S/c1-14-7-8-17(15(2)13-14)21-18-6-4-3-5-16(18)20-11-9-19-10-12-20/h3-8,13,19H,9-12H2,1-2H3



The recommended starting dose of Vortioxetine is 10 mg administrated orally once daily. The dose should then be increased to 20 mg/day, as tolerated. For patients who do not tolerate higher doses, a dose of 5 mg/day should be considered. Vortioxetine is 75% orally bioavailable, with an apparent volume of distribution of 2600L, a plasma protein binding of 98% and a terminal half-life of ca. 66 hours. Vortioxetine is extensively metabolised primarily through oxidation via cytrochrome P450 enzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalysing Vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite. Poor metabolisers of CYP2D6 have approximately twice the Vortioxetine plasma concentration of extensive metabolisers and therefore the maximum recommended dose in known CYP2D6 poor metabolisers is 10 mg/day. Vortioxetine is excreted in the urine (59%) and feces (26%) as metabolites, with a negligible amount of unchanged compound being excreted in the urine up to 48 hours.



The licensed holder of Vortioxetine is H. Lundbeck A/S and the full prescribing information can be found here.