ChEMBL

On 3 October 2013, FDA approved a new drug, bazedoxifene in combination with estrogen (trade name DUAVEE™), for treatment of moderate-to-sever vasomotor symptoms (hot flashes) associated with menopause and the prevention of postmenopausal osteoporosis in women. Bazedoxifene reduces the risk of excessive growth of the uterus (endothermetrial hyperplasia) that can be caused by estrogen.

The license holders are Wyeth Pharmaceuticals, Inc. (a subsidiary of Pfizer Inc.,) based in Philadelphia, Pa.

InChi: InChI=1S/C14H9Cl2N3S2/c15-9-1-2-10(11(16)5-9)13-7-20-14(21-13)12(6-17)19-4-3-18-8-19/h1-5,8,13H,7H2/b14-12+/t13-/m0/s1
Each gram of Luzu Cream, 1% contains 10 mg of luliconazole in a white cream base.

For treatment of Interdigital Tinea Pedis: Luzu Cream, 1% should be applied to the affected and immediate surrounding area(s) once a day for two weeks.

For treatment of Tinea Cruris and Tinea Corporis: Luzu Cream, 1% should be applied to the affected skin and immediate surrounding area(s) once a day for one week.

Pregnancy
Luliconazole is classified as pregnancy category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

The license holder is Valeant Pharmaceuticals, the highlights of the prescribing information can be found here.

Wikipedia: Eslicarbazepine Acetate

On November 8th 2013, FDA approved Eslicarbazepine Acetate (tradename: Aptiom; research codes: Sep-0002093, BIA 2-093; ChEMBL: CHEMBL87992), a prodrug indicated as adjunctive treatment of partial-onset seizures associated with epilepsy.

Epilepsy is neurological disorder characterised by abnormal neuronal activity in the brain. Partial-onset seizures, as opposed to generalised seizures, affect initially only one part of the brain and, depending on the part of the brain that is affected, these seizures will present different symptoms.

Eslicarbazepine (ChEMBL: CHEMBL315985), the bioactive ingredient of the prodrug Eslicarbazepine Acetate, exerts its anticonvulsant activity by blocking the voltage-gated sodium channel (VGSC). VGSC has 3 distinctive states: the resting state, during which the VGSC is closed but responsive to a depolarisation impulse, the open state, during which the channel is open allowing the sodium ion to enter the cell, and the inactivated state, in which the channel is closed again but irresponsive to voltage changes. Eslicarbazepine binds and stabilises the inactive form of the VGSC, preventing its reversion to the resting form and limiting sustained repetitive neuronal firing.

VGSC (ChEMBL: CHEMBL2331043) is a single alpha-subunit with four repeat domains each containing six transmembrane segments. A 3D structure of the VGSC in an open conformation (PDBe: 4f4l) is shown below.



Eslicarbazepine Acetate is a synthetic small molecule with a molecular weight of 296.3 g.mol^-1, an ALogP of 2.4, 3 hydrogen bond acceptors, 1 hydrogen bond donor, and therefore fully compliant with Lipinski's rule of five.
IUPAC: [(5S)-11-carbamoyl-5,6-dihydrobenzo[b][1]benzazepin-5-yl] acetate
Canonical Smiles: CC(=O)O[C@H]1Cc2ccccc2N(C(=O)N)c3ccccc13
InCHI: InChI=1S/C17H16N2O3/c1-11(20)22-16-10-12-6-2-4-8-14(12)19(17(18)21)15-9-5-3-7-13(15)16/h2-9,16H,10H2,1H3,(H2,18,21)/t16-/m0/s1


The recommended starting dosage of Eslicarbazepine Acetate is 400 mg once daily. After one week, the dosage should be increased to 800 mg once daily (recommended maintenance dosage). The maximum recommended maintenance dosage is 1200 mg once daily (after a minimum of one week at 800 mg once daily).

After oral administration, Eslicarbazepine Acetate is mostly undetectable, since it is extensively and rapidly metabolised by hydrolytic first-pass metabolism to its major active metabolite, Eslicarbazepine, corresponding to 91% of systemic exposure. Eslicarbazepine is highly bioavailable with an apparent volume of distribution of 61L for body weight of 70Kg, a relatively low plasma protein binding (< 40%) and an apparent half-life in plasma of 13-20 hours. Other minor active metabolites of Eslicarbazepine Acetate include (R)-Liscarbazepine and Oxcarbazepine, corresponding to 5% and 1% of systemic exposure, respectively. Eslicarbazepine Acetate metabolites are eliminated mainly by renal excretion, in the unchanged and glucuronide conjugated forms, with Eslicarbazepine and its glucuronide accounting for more than 90% of total metabolites excreted in urine.

The licensed holder of Eslicarbazepine Acetate is Sunovion Pharmaceuticals Inc. and the full prescribing information can be found here.

• ChEMBL - Bioactivity data, PK data and molecules.
• PharmaADME - An online resource providing a list ADME related human genes. We used this to build our primary list of ADME Targets, but have also added a couple of extra ones.
• The Human Protein Atlas -  Protein expression data for human ADME Targets.
• ENSEMBL - Orthologue (using the Compara Service) and SNP data for ADME Targets.
• The Göttingen minipig and beagle dog genome predicted ADME Targets. GSK have sequenced the  genomes of these two pharmaceutically significant species. More details on the genomes can be found here.

• Home - Allows user to initiate a compound or protein focused search.
• Orthologues - A table of ADME orthologues. The first column of the table corresponds to the human ADME targets and additional columns correspond to targets found in model organisms.
• Tissues - Protein expression data for human ADME targets.
• Bioactivities - Bioactivity data and PK measurements for all ADME related targets in the system, which are also found in the ChEMBL database.
• Molecules - Distinct set of ChEMBL molecules linked to ADME related targets via the bioactivity data.
• Pharmacokinetic - A cross species comparison of PK data for compounds found in the  ChEMBL database  (see red heatmap image at top).
• About - More details on how to use the system

• Each narrow row corresponds to a compound.
• Each column corresponds to a PK measurement in a specific organism. 
• The PK measurements summarised in this view are Clearance (Cl), Cmax, Bioavailability (f), T1/2, Tmax and Volume of Distribution (Vd). 
• The colour of each cell corresponds to a low, medium and high binned PK measurement, making it easier to compare values across species.
• The columns can be sorted by clicking on the header (see the second column, which corresponds to the Human Clearance data).

ATC Code: J05AE14
Wikipedia: Simeprevir

On November 22^th 2013, the FDA approved simeprevir (Tradename: Olysio; Research Code(s): TMC-435; TMC435350), a Hepatitis C virus NS3/NS4A protease (HCV NS3/NS4A) inhibitor, for the treatment of chronic hepatitis C virus genotype 1 infection, in combination with peginterferon alfa and ribavirin.

Chronic hepatitis C is a prolonged infection that affects the liver and is caused by a small single-stranded RNA virus, which is transmitted by blood-to-blood contact. Chronic hepatitis C is normally asymptomatic, but may lead to liver fibrosis, and thus liver failure.

Simeprevir is an inhibitor of the hepatitis C virus (HCV) serine protease NS3/NS4A (ChEMBLID:CHEMBL2095231; Uniprot ID:A3EZI9, D2K2A8; Pfam:PF02907), a viral protein complex required for the proteolytic cleavage of the HCV encoded polyprotein (UniProt:P27958) into mature forms of the NS4B, NS5A and NS5B proteins. These proteins are involved in the formation of the virus replication complex, and therefore are vital to its proliferation. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively. However, in patients infected with the genotype 1a hepatitis C virus with an NS3 Q80K polymorphism, the effectiveness of simeprevir is slightly reduced, thus, screening for this polymorphism prior to the beginning of therapy is recommended, and alternative therapies should be considered.

There are several protein structures known for HCV NS3 in complex with inhibitors, a typical entry is PDBe:3rc4, as expected from early genome annotation, the NS3 protease has a fold distantly related to the chymotrypsin-like family of serine proteases, and contains the classic Asp-His-Ser catalytic triad.

The -vir USAN/INN stem covers antiviral agents, and the substem -previr indicates it is a serine protease inhibitor. Simeprevir is the third approved agent to target HCV NS3/NS4A, following the approval of Merck's Boceprevir (q.v.) and Vertex's Telaprevir in 2011. Contrary to its predecessors, simeprevir is a natural derived compound, which requires a substantial lower dose (~16x less) for an effective response. It is also once-daily dosed, offering thus a promising alternative therapy for potential non-complying patients. Other compounds in this class in late stage clinical development/registration or earlier stages of development include Genentech's Danoprevir (RG-7227, ITMN-191), Bristol Myers Squibb's Asunaprevir (BMS-650032), Vaniprevir (MK-7009), Schering's Narlaprevir (SCH-900518), Achillion's Sovaprevir (ACH-0141625), Gilead's Vedroprevir (GS-9451), Ciluprevir (BILN-2061), ABT-450, BI-201335, IDX-320, MK-5172, BIT-225, VX-500, ACH-1625 and GS-9256.

Simeprevir (IUPAC Name: (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropylsulfonyl)-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide; Canonical smiles: COc1ccc2c(O[C@@H]3C[C@@H]4[C@@H](C3)C(=O)N(C)CCCC\C=C/[C@@H]5C[C@]5(NC4=O)C(=O)NS(=O)(=O)C6CC6)cc(nc2c1C)c7nc(cs7)C(C)C; ChEMBL: CHEMBL501849; PubChem: 24873435; ChemSpider: 23331536; Standard InChI Key: JTZZSQYMACOLNN-VDWJNHBNSA-N) is a a natural product derived compound, with a molecular weight of 749.9 Da, 9 hydrogen bond acceptors, 2 hydrogen bond donors, and has an ALogP of 4.8. The compound is therefore not fully compliant with the rule of five.

Simeprevir is available as an oral capsule and the recommended daily dose is a single capsule of 150 mg. In HCV-infected subjects, the steady-state is reached after 7 days of once daily dosing and the mean steady-state AUC₂₄ is 57469 ng.h/mL (standard deviation: 63571). Simeprevir should be administered with food, since food enhances its bioavailability by up to 69%. In vitro studies indicated that simeprevir is extensively bound to plasma proteins (greater than 99.9%).

The primary enzymatic system involved in the biotransformation of simeprevir in the liver is CYP3A. Therefore, co-administration of simeprevir with inhibitors or inducers of CYP3A may significantly alter the plasma concentration of simeprevir. In vitro studies indicated that simeprevir is a substrate of P-gp, and is transported into the liver by OATP1B1/3. Following a single oral administration of 200mg, the terminal elimination half-life of simeprevir is 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects. Elimination of simeprevir occurs via biliary excretion, and its metabolites are primarily excreted in feces.

As simeprevir is given as a component of a combination antiviral treatment regime with ribavirin and peginterferon alfa, there is a warning for embryofetal toxicity.

The license holder for Olysio^TM is Janssen Pharmaceuticals, and the full prescribing information can be found here.

https://www.ebi.ac.uk/chemblws2