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.



Effect of ring substitution5


Effect on rotatable bond6


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



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  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.



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


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.


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.





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.


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


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


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HepatoChem Presenting at the ACS Meeting in Boston, MA

Dr Ryan Buzdygon will be presenting “Late-stage functionalization platform for lead optimization and diversification: Generation of high value compounds directly for biological testing” at ACS Boston. Stop by on Wednesday August 19th during the General Posters Session for the Division of Medicinal Chemistry from 7:00 PM – 9:00 PM in the Ballroom at the Boston Convention & Exhibition Center to hear about our late stage diversification platform.

HepatoChem @ Drug Discovery Chemistry Conference

HepatoChem will be present at the tenth annual Drug Discovery Chemistry on April 21-23, 2015 in San Diego. Please come and see us at the booth 34.

HepatoChem and XenoTech Announce Exclusive Partnership


Lenexa, KS, August 19th, 2014 — XenoTech announces an exclusive partnership with HepatoChem to offer fast and cost-effective metabolite production from bioactive small molecules. Based on an innovative and proprietary chemistry platform, the technology enables convenient and timely assessment of critical metabolite and toxicity issues. According to XenoTech’s Vice President of Commercial Operations, Christian Darabant, “the value of rapid metabolite synthesis for assessing clinical risk can be measured directly by comparison with the approximate $2 million per day cost impact of each day of delay in a drug’s development.”
Metabolite synthesis is critical in the drug development process as it allows researchers to accurately evaluate metabolites in safety toxicity as well as promoting identification and isolation of pharmacologically active metabolites. According to Marc Bazin, HepatoChem’s CEO, “current technologies are designed to identify metabolites but are unable to produce testable quantities of metabolites. Consequently, metabolite studies are delayed (a calculated risk) in the drug delivery process; having access to milligram quantities of drug metabolite permits resolution of many of the fundamental questions surrounding small molecule metabolism. The biomimetic technology speeds up metabolite studies to allow rapid improvement of the metabolic properties of drug candidates.” XenoTech’s Executive Vice President & COO, Jason Neat, further explains, “Combining XenoTech’s ability to effectively elucidate metabolite formation through biological processes with the ability to efficiently produce milligram quantities of metabolites of interest for further evaluation is a benefit we must bring to our clients. By pairing XenoTech’s in vitro DMPK expertise with HepatoChem’s innovative platform, we are able to offer a tremendous and comprehensive solution to our customers for risk mitigation.”

The innovative technology uses biomimetic catalysts to mimic oxidative metabolism which synthesizes metabolites from the parent drug. The catalytic conditions are as selective as enzyme specificity achieved with microsomes or hepatocytes yet have the advantage of enabling metabolite production in milligram quantities. This unique system offers a highly competitive, higher-yield, cost-effective alternative to biological metabolite synthesis, facilitating knowledge early in the development process for informed program decision-making. Researchers around the world will benefit from this synergistic pairing of XenoTech’s distinguished expertise and holistic approach to drug metabolism research with HepatoChem’s unique, effective and efficient biomimetic oxidation platform. Biomimetic metabolite synthesis is now offered as both a service, with the work performed by the expert scientists at XenoTech and HepatoChem or for in-house work as a product, allowing customers the freedom to synthesize metabolites in their own laboratories via the BMO™ Kit.

About XenoTech
XenoTech, LLC is a global Contract Research Organization with unparalleled experience and expertise in evaluating drug candidates, nutraceuticals, cosmetics, food additives and other compounds widely known as xenobiotics, substrates, inhibitors and inducers of cytochrome P450, UGT and other drug metabolizing enzymes and drug transporters. The company offers a variety of in vitro and in vivo safety assessment studies for drug candidate evaluation, as well as an extensive selection of products for drug metabolism research. XenoTech’s product selection includes a wide-range of high quality standard reagents, from subcellular fractions and hepatocytes to recombinant enzymes, substrates and metabolites. The company can also prepare and deliver custom-designed products and services in respnose to client requests. For additional information, please refer to the company’s website at or call (913) 438-7450.

About HepatoChem
HepatoChem, Inc. of Beverly, Massachusetts was founded in 2008, is a life science company that has developed its technology platform through a partnership with Princeton University. HepatoChem focuses on early stage development with a game-changing, proprietary chemistry platform that enables fast and cost-effective metabolite production from bioactive small molecules. The HepatoChem technology enables assessment of critical metabolite and toxicity issues early in the R&D continuum, reducing the risk of failure in clinical development of drug candidates. For more information, visit

HepatoChem at the Drug Discovery & Therapy World Congress 2014

HepatoChem will be attending the Drug Discovery & Therapy World Congress 2014 from June 16 – June 19 in Boston MA. The event will be held at the Hynes Convention Center located at 900 Boylston Street. Be sure to stop by and visit us at booth B6!

HepatoChem at the Massachusetts CRO/CMO Symposium


HepatoChem will be attending the Massachusetts CRO/CMO Symposium on Monday May 5 2014. The event will be held at the Burlington Marriott at 1 Burlington Road, Burlington MA. Be sure to stop by and visit us!

HepatoChem at the New Jersey DMDG

NJACS-atom-logo-44x2191HepatoChem will be attending the New Jersey Drug Metabolism Discussion Group Spring Symposium on May 1, 2014 at The Palace at Somerset Park in Somerset, NJ. Be sure to visit us to hear about our latest technologies!

HepatoChem, Inc. Designs Innovative Tools for the Life Sciences Industry

HepatoChem has developed extensive capabilities to quickly survey organo-metallic chemistry systems and design innovative tools for the pharmaceutical industry. It has most recently commercialized the BMO (BioMimetic Oxidation) Kit, which utilizes rapid one step biomimetic chemistry to generate useful quantities of drug candidate metabolites.  Applying a similar developmental approach, HepatoChem is now providing unique tools for the instant and flexible diversification of biologically active small molecules. These tools are largely centered on fluorination chemistry. HepatoChem is currently working with Vertex, a local biotech based in Boston, MA, to develop tools to allow for fast discovery of fluorinated analogues of small molecules, which Vertex scientists will employ in their own projects.

HepatoChem Co-founder and President Marc Bazin stated “Our work with Vertex is an extraordinary opportunity to demonstrate the versatility of HepatoChem’s platform. We are all committed to the development of innovative tools, such as chemical diversification kits, for companies that are seeking to discover and develop new medicines. “

About HepatoChem, Inc.

Founded in 2008, HepatoChem is an early-stage company that offers innovative services and products to the pharmaceutical industry. Our core expertise is organo-metallic catalysis and high-throughput compound analysis. HepatoChem received the Accelerator Loan from Mass Life Sciences Center in 2012 and is located in Beverly, MA at NorthShore InnoVentures (NSIV).


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