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.

New Drug Approvals 2013 - Pt. XIII - Dolutegravir (TivicayTM)

ATC code: J05AX12







On 12 August, the FDA approved a further drug for the treatment of HIV-1 infection, Dolutegravir (Tradename: Tivicay). Dolutegravir also known as S/GSK-1349575, is an HIV-1 integrase inhibitor. The drug has been approved for treatment of treatment-naïve as well as treatment-experienced HIV-infected adults including those who have been treated with other integrase inhibitors. In addition, Dolutegravir can be used for the treatment of children aged 12 years or older and weighing at least 40kg who have not been treated with integrase inhibitors, but are either treatment-naïve or treatment –experienced.



HIV, a lentivirus, infects vital cells in the human immune system such as helper T. cells (CD4+ T cells) and macrophages. The disease is responsible for millions of death every year, especially in Sub-Saharan Africa where treatment complications are enhanced by co-infection with tuberculosis and poverty. The approval of a new antiviral agent like Dolutegravir, will enhance treatment of the disease and improve the quality of people’s lives.



Dolutegravir is an inhibitor of HIV-1 integrase responsible for the insertion of the viral DNA into the host chromosomal DNA. The drug interferes with replication of HIV by preventing the viral DNA from assimilating into the genetic material of the human T cells. An example of a 3D structure of the enzyme’s core domain (PDBe: 3vqa) is shown below.

HIV-1 integrase (ChEMBLID: CHEMBL3471, UniProt Accession: Q72498)  is an attractive target for drug design. It is one of three enzymes of HIV (others are Reverse Transcriptase and the Protease) that consists of three main domains with specific functions. The N-terminal domain characterized by the His2Cys2 motif chelates zinc, the core domain consists of the catalytic DDE motif important for the activity of the enzyme, and the C-terminal domain, with an SH3-like fold, that binds DNA nonspecifically. There are a variety of crystal structures of the different domains of HIV-1 integrase reported in PDBe (Protein Data Bank in Europe)

Dolutegravir , ChEMBLID: CHEMBL1229211 (C20H19F2N3O5, IUPAC Name: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro-2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide, Canonical smiles: CC1CCOC2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)O) has two chiral centers, molecular weight of 419.12, 2 hydrogen bond donors, 6 hydrogen bond acceptors, 3 rotatable bonds, Polar surface area of 99.18 and alogP of 0.3. Dolutergravir is orally administered since it does not violate Lipinsik’s ‘Rule of Five’. The drug may be taken with or without food. For treatment-naïve or treatment-experienced with integrase transfer inhibitor (INSTI) – naïve adults and children the recommended dose is 50mg once. A dose of 50mg twice daily is recommended when dolutegravir is co-administered with potent UGT1A/CYP3A inducers like efavirenz, fosamprenavir/ritonavir, Tipranavir/ritonavir or rifampin.



The license holder for Dolutegravir is ViiV Healthcare, an HIV joint venture between GSK, Pfizer Inc and Shionogi. The full prescribing information can be found here.

New Drug Approvals 2013 - Pt. XIV - Tecfidera™

ATC Code: N07XX09 (2014)

Wikipedia: Dimethyl Fumerate

ChEMBL: CHEMBL2107333

On March 27th the FDA approved Dimethyl Fumarate (DMF, trade name TECFIDERA™) for the treatment of adults with relapsing forms of multiple sclerosis (MS). DMF and the metabolite, monomethyl fumerate (MMF), activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway via inhibition of Kelch-like ECH-associated protein 1 (KEAP1, cytosolic inhibitor of Nrf2). 

Target(s)

The KEAP1 (CHEMBL2069156) is a naturally occuring cytosolic inhibitor of Nrf2 and DMF/MMF acts through chemical modification of KEAP1.



The NrF2 pathway is the primary cellular defence against the cytotoxic effects of oxidative stress. After translocation to the nucleus, Nrf2 heterodimerizes with MafF, MafG, and MafK. The combined heterodimer binds to antioxidant/electrophile response element (ARE/EpRE) and subsequently initiates transcription of these genes.



KEAP1 acts as the cytosolic anchor of Nrf2, sequestering Nrf2 in the cytoplasm during basal conditions. In addition KEAP1 contains a nuclear export signal and it is hypothesised to be the primary redox sensor. Thus DMF mediated inhibition of KEAP, leads to an increase of NrF2 translocation and increase in transcription of ARE/EpRE. This is hypothesized to be the working mechanism of DMF/MMF in MS. In addition, MMF has been shown to be an agonist of the nicotinic acid receptor (CHEMBL3785).

Dimethyl Fumarate (CHEMBL2107333 ; Chemspider : 553171;  Pubchem : 99431554 ) is a small molecule drug with a molecular weight of 144.1 Da, an AlogP of 0.49 , 4 rotatable bonds and does not violate the rule of 5.

Canonical SMILES : COC(=O)\C=C\C(=O)OC

InChi: InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+

Dosage

The recommended starting dose of TECFIDERA is 120 mg twice daily, for 7 days. Subsequently the dosage should be increased to a 240 mg twice daily maintenance dose. Tecfidera can be taken with or without food.



Metabolism

In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma.



Excretion

Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the TECFIDERA dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively. Trace amounts of unchanged MMF were present in urine.



The terminal half-life of MMF is approximately 1 hour and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with repeated dosing.



The license holder is Biogen Idec. the full prescribing information can be found here.