Archive for Sci Update

PhotoRedOx Box Setup

Interest in photochemistry has been growing exponentially in recent years. Numerous new applications using visible-light photoredox catalysis have been discovered. These catalytic systems can perform many types of bond formations using various substrates which are valuable new tools for synthetic chemists.

However photoredox chemistry setup necessitates to the use of a light source (blue light) and apparatus that are not standard yet in an organic chemistry laboratory. Many chemists have made their own setup and tried to reproduce literature chemistry with more or less success. As a result the implementation of photoredox chemistry is slow and organic chemists are still hesitant to try these important new tools. Therefore, the need for a simple and robust device to perform visible-light photoredox catalysis has become increasingly important.

EvoluChem™ PhotoRedOx Box

The EvoluChem™ PhotoRedOx Box was designed with one main objective: To allow any chemist to easily perform multiple photoredox reactions in a reproducible environment. Our photochemistry device provide an even light distribution to all reaction samples allowing consistent and reproducible reactions. A cooling fan allows even temperature distribution and keeps the chamber near room temperature during long reaction runs.  The device easily fits on standard stir plates, allowing for consistent stirring.    Sample holders are compatible with vials ranging from 0.3 ml to 20 ml vials.

Unique Design

The PhotoRedOx Box is using a unique geometry of mirrors to irradiate multiple samples simulatanously for parallel chemistry setup while limiting the thermal effect of the light source. This design results into a compact and efficient photoredox device which can be easely set on any standard stir plate.

light_mirrors

The removable lamp adapter allows easy switching from the standard kessil™ blue 34W LED lamp to many other light sources.

Fit multiple vial formats

Organic chemists needs to be able to use different reaction vial sizes depending on the scale and the number of the reaction to be performed. The PhotoRedox Box can virtually fit any type of vials including 0.3ml crimped vials (6 x 32mm), 2ml HPLC vials (12 x 32mm), 1DRAM (15 x 45mm), Microwave vial 2-5mL (17 x 83mm), 2DRAM (17 x 60mm) and 20ml scintillation vials (28 x 61mm). This feature allows quick and consistent scale up from screen reactions to larger scale with preset sample positions removing the guess work on sample placement distance from the light source.   When using 0.3 ml vials, 32 reactions can be performed in parallel in the photochemical device.  At 20 ml, two reactions can be run in duplicate.

Reproducibility

With the EvoluChem photomethylation kit, we have demonstrated the reproducibility of both the photomethylation kit and the device.  Using a photomethylation of buspirone as test reaction, 16 vials spread through the 0.3 ml vial sample holder for Trial #1 results in 53% (+/-2 %) conversion. See figure.  For a second trial with 16 reaction vials we observed an average conversion of 56% (+/-2 %) for the mono-methylated product.

Test reaction (Methylation)

 photomethylation_reaction

Percentage of mono-methylation product

by reaction vial position

reproducibility_photomethylation

Average- 53% +/-2%

Reaction conditions:

Each reaction vial contains Ir(dF-CF3-ppy)2(dtbpy)[PF6] (0.1 µmol), tert-butylperacetate solution (12.5 µmol) and a stir bar sealed under inert atmosphere.  To each vial was added 50 µl of 0.05 M buspirone solution in 1:1 trifluoroacetic acid/acetonitrile sparged with nitrogen stream.  Reaction mixture irradiated with Kessil 34 W blue LED for 18 hr using EvoluChem photochemical device.

Ir/Ni visible-light photoredox catalysis exploration

A significant number of traditional cross-coupling reactions have been performed using photochemistry.  In many cases, this involves using an Iridium photocatalyst like Ir(dF-CF3-ppy)2(dtbpy)[PF6] to activate a sluggish catalytic cycle (Ni) in the presence of a ligand and base.  Many reactions conditions have been reported in the literature using a wide range of reagents.  However, often these reactions are highly substrate, solvent and base specific. We describe several examples from literature that haven been modified to be performed in kit form in our PhotoRedOx box device.

Screening reaction conditions

To reduce the amount of catalysts, reagents and substrate used during reaction screening, we perform reaction condition at 5 µmol substrate in 100 µl solvent with 0.1 µmol Ir catalyst and 0.5 µmol premixed Ni-dtbbpy with 3 equiv. of base with stir in a vial capped under inert atmosphere.

C-C coupling through decarboxylation

The decarboxylative sp3-sp2 cross-coupling of amino acids and other activated carboxylic acids with aryl halides is a powerful tool for the synthesis of new organic molecules.

Zuo_Article

See Reference:  Zuo, Z., et. al. Science  2014, 345, 437-440.

The success of this type of reaction relies on finding the right combination of Ir catalyst / Ni ligand, base and solvent. We performed the cross-coupling reaction between the substrates Boc-Val and 4-bromoacetophenone using 100 µl screening reaction condition as described previously. The results shows that the conversion is highly dependent on base. In this case Cs2CO3 and K3PO4 promote the reaction while DABCO and DBU do not.

BocVal_Cs2CO3

C-N coupling with secondary amines

Cross-coupling reaction between halide aryl and secondary amine aliphatic amine are possible with Ir/Ni photoredox catalysis.

corcoron_article

See reference:  Corcoron, E. et. al., Science 2016, 353, 279-283.

Like decarboxylative sp3-sp2 cross-coupling, the success of this C-N cross-coupling relies on finding the right combination of Ir catalyst / Ni ligand, base and solvent. For example the cross-coupling reaction between the substrates pyrolidine and 4-bromoacetophenone (see below) is highly dependent of the used base. In that case DABCO promotes the reaction when Cs2CO3, K3PO4 and DBU don’t.

 pyrolidine_dabco

C-N coupling with aromatic amines

Cross-coupling reaction between halide aryl and aromatic amine are possible with Ir/Ni photoredox catalysis.

Oderinde_article

See reference:  Oderinde, M., et. al. Angew. Chemie, 2016, 55, 13219-13223

In that case aniline and 4-bromoacetophenone are reacting in presence of DBU or DABCO.

Aniline_DBU

C-N coupling with secondary and aromatic amines

With the indoline as substrate the reaction works better with K3PO4. Indole_k3po4

Results summary

Selection of base and solvent important to find condition for appropriate coupling (5 µmol per reaction /100 µL scale)

Screen Reaction 20x Scale-up

Reaction condition identified in the screen can be directly transposed to larger scale. For example the The decarboxylative sp3-sp2 cross-coupling of Boc-Val and 4-bromoacetophenone can be scaled up from 5 µmol to 100 µmol with 90% conversion.

bocvalscaleupExperimental Details:  In duplicate in a 4-ml vial equipped with a teflon septa and 2×7 mm stir bar, were weighed NiCl2-dme (2.2 mg, 10 µmol, 0.1 mol %), dtbbpy (2.68 mg, 10 µmol, 0.1 mol %), Ir(dF-CF3-ppy)2(dtbpy) (2.24 mg, 2 µmol, 0.02 mol %),  and Cs2CO3  (97.8 mg, 300 µmol, 3 equiv.). To this vial was added a 2.0 ml solution in DMF containing Boc-Val-OH (10.85 mg, 100 µmol, 1 equiv.) and 4-bromoacetophenone (9.95 mg, 100 µmol, 1 equiv.).  The solution was sparged with nitrogen via submerged needle for 5 minutes and vial was placed in EvoluChem PhotoRedOx Box with blue Kessil LED and irradiated for 24 hrs.  Reaction progress was monitored by LC-MS.  After 24 hours, conversion was greater than 90%.  No additional product was observed at 48 hrs.

Iridium/Nickel Photoredox Kits

In order to facilitate the screening of common photochemistry reactions, EvoluChem has released a series of kits combining common Iridium, nickel, ligand and base combinations to achieve the following transformations.

Ir/Ni base and solvent screen kit: HCK1009-01-002

This kit is designed to screen reaction conditions with 8 different bases, Iridium catalyst Ir(dF-CF3-ppy)2(dtbbpy)[PF6] and Ni ligand dtbbpy. This is the quickest way to find which base will work with your substrates.

Kit reagent map

Cs2CO3 K3PO4 K2HPO4 KOH Li2CO3 K2CO3 DABCO DBU
Solvent A

2 sets of 8 bases per kit (16 total vials)

HCK1009-01-002

Solvent B

 

Ir/Ni base and ligand screen kits:

HCK1009-01-003/ HCK1009-01-004

This kit is designed to screen both bases and Ni Ligand with Iridium catalyst Ir(dF-CF3-ppy)2(dtbbpy)[PF6].

It is recommended for difficult or complex substrates.

Cs2CO3 K3PO4 K2HPO4 K2CO3 DABCO DBU
dtbbpy

2 sets of 4 bases and 4 ligands per kit

(32 total vials)

HCK1009-01-003

2 sets of 6 bases

and 4 ligands per kit

(48 total vials)

HCK1009-01-004

bphen
(MeO)2bpy
biox

 

 

Ir/Ni base and Ir catalyst screen kit: HCK1009-01-005

This kit is designed to screen both bases (3) and Iridium catalysts (6) with Ni Ligand.

It is recommended for difficult or complex substrates.

Cs2CO3 CsF DBU
Ir(dF-CF3-ppy)2(dtbbpy)PF6

2 sets of 3 bases and 6 Ir catalysts per kit

(36 total vials)

HCK1009-01-005

Ir(dtbbpy)(ppy)2PF6
 Ir(dF-CF3-ppy)2(bpy)PF6
Ir(dF-ppy)3
Ir(dmppy)2(dtbbpy)PF6
Ir(dF-CH3-ppy)2(dtbbpy)PF6

 

Amide Coupling in Medicinal Chemistry

In recent years, amide coupling has become the most frequently used reaction in medicinal chemistry1.  Found as the backbone of proteins, the amide bond is nominal formed by the condensation of a carboxylic acid and an amine.  Due to a nearly unlimited set of readily available carboxylic acid and amine derivatives, amide coupling strategies can be an efficient approach for medicinal chemists to generate novel compounds.  As a result of this utility, a nearly unlimited set of reagents and protocols have been development to afford this simple transformation of amide bond formation2,3.

Amide Bond Formation

amide_bond_formation

The most common method for formation of an amide bond is the condensation of a carboxylic acid and an amine.  Generally, the carboxylic acid needs to be activated in order to react with the amine while remaining reactive functional groups need to be protected.  This process occurs in two steps in either one pot with direct reaction of the activated carboxylic acid or in two steps with isolation of an activated “trapped” carboxylic acid with reaction with an amine.

Two step peptide bond formation

two_step_peptide

The carboxylate reacts with the coupling reagent yielding a reactive intermediate which can often be isolated or used immediately with an amine to form an amide bond.  A wide variety of reagents have commonly been used to generate the activated carboxylic acid such as an acid halide (chloride, fluoride), azides, anhydrides, or carbodiimides.  Additionally, active esters such as pentafluorophenyl or hydroxysuccinimido esters can be prepared as reactive intermediates.  Reactive intermediates derived from generation of acyl chlorides or azides are highly efficient for amide coupling; however, their harsh formation and high reactivity often limits use with complex substrates or amino acids.  A broadly applicable method for the formation of amide bonds use carbodiimides such as DCC (dicyclohexylcarbodiimide) or DIC (diisopropylcarbodiimide) for activation.  Additives are often required to improve the efficiency of the reactions especially for solid-phase synthesis.

common_carbodiimides_additives

To avoid side reactions involving the substituents on the two coupling components, it is often necessary to carefully select the appropriate peptide-coupling reaction condition.   One common problem with the use of carbodiimides is the racemization of amino acids.   To remedy this, two classes of coupling reagents:  Phosphonium and aminium reagents represent significant improvements over carbodiimide methods.

Common Aminium reagents

common_aminium_reagents

Common Phosphonium reagents

common_phosphonium_reagents

Aminium salts are very efficient peptide coupling reagents with quick reaction times and minimal racemization.  With the addition of an additive such as HOBt, racemization can be completely eliminated.  Aminium reagents are used in equal molarity to the carboxylic acid to prevent excess reagent reacting with the free amine of the peptide preventing coupling.  Phosphonium salts react with carboxylate requiring usually 2 equivalent of base.  (such as DIEA).  One key advantage for the use of phosphonium salts over iminium reagents is that phosphonium does not reactive with the free amino group of the amine component.  This allows couplings to occur in equimolar relation between the acid and amine, highly advantageous in situations such as the intramolecular cyclization of linear peptides or examples where excess of valuable amine component is discouraged.

Choosing the correct reaction for your needs:

While amide bond formation is a straightforward reaction, the choice of suitable reagents for an individual coupling of a complex carboxylic acid and amine may be a difficult decision.  A variety of factors can be involved in finding the optimal peptide coupling reaction.  Unanticipated side reactions or rearrangements, low conversions, solubility issues, or incompatibility with additional synthetic steps can all hinder what would appear to be a straightforward amide coupling reaction.  As such, it is often necessary to draw from the large number of available reagents and protocols to find the optimal reaction condition.  Screening a selection of reagents can often find a suitable reaction for any amide coupling.

 

References:

 

1.  Brown, Dean G., Bostrom, Jonas, “Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry:  Where Have All the New Reactions Gone?” J. Med. Chem., 2015, ASAP.

2.  El-Faham, Ayman; Albericio, Fernando, “Peptide Coupling Reagents, More than a Letter Soup” Chem. Rev., 2011, 111, 6557.

2.  Pattabiraman, Vijaya R., Bode, Jeffrey W. “Rethinking Amide Bond Synthesis” Nature, 2011, 480, 471.

Magic methyl in medicinal chemistry

Methyl groups are very common in drug molecules. As reported by Heike Schonherr and Tim Cernak1, more than half of the top-selling drugs contains a CH3. A simple substitution of a C-H with a methyl can increase the potency of a compound by more than 100-fold.

The effect of C-H methylation primarily affects the conformation of the original molecule.  Based on this reported statistical analysis2 the effect of methyl can be equally positive or negative. However a positive effect could be decisive in a drug discovery program.

Effect of ortho substitution3,4.

ortho_methylation1

ortho_methylation2

Effect of ring substitution5

ring_methylation

Effect on rotatable bond6

bond_methylation

Even if the methyl can be seen as a potential hot spot for metabolism. The addition of the methyl next to a metabolism position can improve metabolic stability.7

Methyl_stability

 

Contact us at info@hepatochem.com

 

  1. Heike Schonherr and Tim Cernak, Angew. Chem Int. Ed. 2013, 52, 12256-12267
  2. C. S. Leung, S. S. F. Leung, J. Tirado-Rives, W. L. Jorgensen, J. Med. Chem. 2012, 55, 4489 – 4500.
  3. F. Berardi, C. Abate, S. Ferorelli, A. F. de Robertis, M. Leopoldo, N.A. Colabufo, M. Niso, R. Perrone, J. Med. Chem. 2008, 51, 7523 – 7531.
  4. J. Y. Hwang, D. Smithson, F. Zhu, G. Holbrook,M. C. Connelly, M. Kaiser, R. Brun, R. K. Guy, J. Med. Chem. 2013, 56, 2850 – 2860.
  5. P. J. Coleman and coll. , Chem- MedChem 2012, 7, 415 – 424.
  6. G. F. Costello, R. James, J. S. Shaw, A.M. Slater, N. C. J. Stutchbury, J. Med. Chem. 1991, 34, 181 – 189.
  7. R.W. Friesen and coll., Bioorg. Med. Chem. Lett. 1998, 8, 2777 – 2782.

 

 

Buchwald palladium precatalysts

Palladium based catalysis is the most used tool to perform the formation of C-C, C-O and C-N. There are many sources of palladium such as PdOAc2, PdCl2 or Pd2dba3. However the related methods do not always allow sufficient conversion.

Palladium precatalysts is an efficient solution to generate in-situ the LnPd(0) needed for the reaction. These precatalysts are generally air and moisture stable.

The first palladacycle precatalyst has been reported by Herman and Beller in 19951. Since then Buchwald laboratories has developed several types of palladium.

The first generation of Buchwald palladium precatalysts are phenethylamine derivatives. In presence of a base the LPd(0) can be generated in-situ.

1st_generation_precatalysts_activation

 

The second generation of Buchwald palladium precatalysts are 2-aminobiphenyl derivatives. These precatalysts can be activated at room temperature.

2nd_generation_precatalysts_activation

The third generation of Buchwald palladium precatalysts are methylsulfonate salt of 2-aminobiphenyl derivatives. These precatalysts are compatible with bulky ligands and show longer stability in solution.

3rd_generation_precatalysts_activation

The fourth generation of Buchwald palladium precatalysts are methylsulfonate salt of 2-methylaminobiphenyl derivatives. These precatalysts are compatible with bulky ligands and show longer stability in solution.

4th_generation_precatalysts_activation

 

try_precatalyts_kit

 

1 Herman,W.A.; Beller,M. Angew. Chem. Int. Ed., 1995, 34, 1844-1848.

 

Why is fluorine so attractive to medicinal chemists?

In medicinal chemistry, fluorine substitution of alkyl or aryl hydrogen is an increasingly popular strategy to optimize lead compounds. Fluorine offers unique properties. It is almost as small as a hydrogen but very electronegative. The C-F bond is highly polarized.

Conformation effect of fluorine

The polarity of the C-F bond influences the conformation of aliphatic systems.

conformation_fluorine

It is generally accepted that fluorine can interact with hydroxyl, amine and amide functions through hydrogen bond interaction and induce specific conformation.

hydrogen_bond_fluorine

Influence on pKa, permeability and pharmacokinetic properties of fluorine

The electron-withdrawing properties of fluorine can reduce pKa of amines and make them less basic. The similar effect is observed on carboxylic acids and make them more acidic. The change in pKa will influence conformation, potency, permeability, and pharmacokinetic properties.

pKa of fluorinated acids, alcohols or amines

CH3CO2H      4.8       CH2FCO2H    2.6

(CH3)2CHOH 17.1     (CF3)2CHOH  9.3

CH3CH2NH2  10.7      CF3CH2NH2   5.7

Improve metabolic stability

Because of the strength C-F bond, fluorine substitution of a hydrogen is a common way to improve stability. It can be done in both aliphatic and aromatic systems. Fluorine will also increase metabolic stability of electron-rich aromatic ring.

 

Learn how to add fluorine in your lead compounds here.

 

Read more
Eric P. Gillis, Kyle J. Eastman, Matthew D. Hill, David J. Donnelly, and Nicholas A. Meanwell, Applications of Fluorine in Medicinal Chemistry, J. Med. Chem., 2015
http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00258

 

Contact us at info@hepatochem.com

Unusual Biotransformation of a Pyrrolotriazine Heterocycle

Biotransformations can be diverse and not limited to simple oxidation or dealkylation. An oncologic agent, The BMS-690514, is an example of unexpected metabolism. This compound undergoes multiple biotransformations, among them are P450 mediated oxidations of its heterocycle pyrrolotriazine group. Two major metabolites A and B are resulting from + O biotransformation.  However if the metabolite A shows a hydroxylation of the heterocycle, the metabolite B seems to undergone a unusual rearrangement. The isolation of that metabolite demonstrated the formation a hydroxypyridotriazine group.

This structure was confirmed using NMR spectrometry. The metabolism study of deuterium and tritium isotope label at the oxidized position showed that the label was retain during the formation of the metabolite A and lost during the formation of the metabolite B. The authors concluded that this metabolite was formed via epoxidation.

Haizheng Hong et al. Chem. Res. Toxicol. 201124, 125-134.

Mitochondrial Liabilities Assay and Metabolism with ICDD

Several recent papers have highlighted the importance of identifying mitochondrial liabilities to completely assess the toxicity potential of a drug (1-3).  Mechanisms by which drugs induce organ toxicity include the production of reactive metabolites (4).  Examples such as high-dose acetaminophen, which produces metabolites toxic to the mitochondria are found in the literature (5-8). 

Metabolites or cocktails of metabolites obtained through the Hepatochem technologies may act on one or several mitochondrial targets to induce mitochondrial impairment.  ROS production or reduced anti-oxidant defenses, perturbation of the bioenergetic balance, induction of permeability transition, depletion of mtDNA or reduced mitochondrial mass are some of the various targets that may induce mitochondrial dysfunction, loss of susceptible cell integrity & ultimately organ malfunctions and/or failure (7,9-12).  Using the MitoSafe line of functional bioassays developed by ICDD will demonstrate whether metabolites of your drugs induce mitochondrial liabilities in live-cell models.  Mitochondria toxicity is most readily expressed clinically by hepatic injury & cardio-toxicity, which can both be flagged through the study of your compounds and their metabolites with the MitoSafe bioassays.

Don’t hesitate to ask questions to our mitochondria experts:Contact@icdd-sas.com

1- Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Toxicol Sci. 2007 ;97(2):539-47.

2- Dykens JA, Will Y. Drug Discov Today. 2007 ;12(17-18):777-85.

3- Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B.  J Hepatol. 2011 ;54(4):773-94.

4- Liebler DC, Guengerich FP.  Nat Rev Drug Discov. 2005 ;4(5):410-20.

5- Kostrubsky SE, Strom SC, Ellis E, Nelson SD, Mutlib AE. Chem Res Toxicol. 2007 ;20(10):1503-12.

6- Jaeschke H, McGill MR, Williams CD, Ramachandran A.  Life Sci. 2011 25;88(17-18):737-45.

7- Song Y, Shi Y, Yu H, Hu Y, Wang Y, Yang K. Toxicol Lett. 2011 ;202(1):55-60.

8- Chaudhuri L, Sarsour EH, Goswami PC. Environ Int. 2010 ;36(8):924-30.

9- Siu WP, Pun PB, Latchoumycandane C, Boelsterli UA.  Toxicol Appl Pharmacol. 2008 ;227(3):451-61.

10- Bai J, Nakamura H, Ueda S, Kwon YW, Tanaka T, Ban S, Yodoi J. J Biol Chem. 2004 ;279(37):38710-4.

11- Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H.Toxicol Appl Pharmacol. 2011 ;251(3):226-33.

12- Zou W, Roth RA, Younis HS, Burgoon LD, Ganey PE. Toxicology. 2010 ;272(1-3):32-8. 

Metalloporphyrin Reactivity

Metalloporphyrins are powerful catalysts capable of a wide variety of chemical transformations. Simple modifications to the catalyst system allow for tuning a catalyst for relatively mild oxidations or more difficult to oxidize substrates. Recently, Zhdankin and coworkers have demonstrated a co-catalyst system with an iron porphyrin with a mixture of iodobenzene and oxone allowing for the quantitative conversion of anthracene to anthroquine (1). This system has also shown promise for the oxidation of alkanes and alkenes such as tetrahydronaphthalene, dihydroanthrane and styrene in moderate yields.

With tuning of the catalyst and reaction conditions, metalloporphyrins are also capable of mild oxidations such as sulfoxidations even in the presence of reactive C-H or alcohol functional groups. Huang and coworkers have used a manganese porphyrin-hypochlorite system for the selective oxidation of glycosyl sulfides to the sulfoxides with high diasteromeric excesses (2). Very little sulfone formation and no oxidation on the sugar occurred. These two recent examples show both the selectivity and powerful oxidation capabilities of metalloporphyrins.

1. Yoshimura, A.; Neu, H. M.; Nemykin, V. N.; Zhdankin, V. V., Metalloporphyrin/Iodine(III)-Cocatalyzed Oxygenation of Aromatic Hydrocarbons. Advanced Synthesis & Catalysis 2010, 352, (9), 1455-1460.
2. Huang, J. Y.; Li, S. J.; Wang, Y. G., Selective Oxidation of Glycosyl Sulfides to Sulfoxides with Sodium Hypochlorite and Catalyzed by Metalloporphyrins. Journal of Carbohydrate Chemistry 2010, 29, (3), 142-153.

Structure-Activity Relationship of Hepatotoxicity

Drug induced liver injury is a major cause for withdrawing a drug from development or more dramatically from the market. In a recent article, Dr. Dennis J. Pelletier et Al. performed a SAR study of hepatotoxicity. They used the data from literature and built a structure searchable database. The resulting database was analyzed to identify the chemical structures associated with liver toxicity. Data from over 1266 compounds were collected and a SAR of 38 chemical structures was developed. An interesting chemical structure highlighted as a potential liver toxin is the thiophene ring. Metabolic activation of thiophene leads to a reactive intermediate that can undergo Michael type addition with cellular nucleophiles. See figure below.

 

Interestingly, hepatotoxicity is often due to an activation of the drug resulting from Phase I metabolization. Moreover, this kind of reactive metabolite is present at low levels in the blood stream which makes them difficult to be detected.
Biomimetic technology can allow for the production of such metabolites for biological and toxicology studies which could reduce the drug development attrition due to liver toxicity.
Dennis J. Pelletier et Al.; Chem. Res. Toxicol., 2010, 23, 1215-1222

SMARTCyp: a Wed Based CYP-Mediated Metabolism Prediction Tool

We would like to bring to your attention to a new metabolism tool available online. Lars Olsen et al. have developed a web based platform that predicts potential sites of metabolization. This free tool is the first web service for prediction of CYP-mediated metabolism. Based on a recent publication from Simon E. Ward et al. where they describe the metabolism pathway of a novel clinical AMPA receptor positive modulator, we tested the prediction tool and the result confirmed the potential utility of this application for the prediction of CYP-mediated metabolism.

Patrik Rydberg, David E. Gloriam and Lars Olsen. Bioinformatics 2010, 26, 2988-2989. www.farma.ku.dk/smartcyp

Simon E. Ward et al. J. Med. Chem. 2010, 53, 5801-5812