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Working With Synthesis

July 28, 2010 16:19 by EmileBellott

  



ThisAugust, Pharmaceutical Manufacturing and Packing Sourcer (PMPS) will publish an article by AsisChem scientists Guillermo Morales, Bryan Roland, and Emile Bellott, entitled: “Working With Synthesis” ( August, 2010, p70 )  Some of our findings and main points are summarized below:

For the past two decades, the industry buzz has been about ‘pipeline productivity’. The well-known graphic showing exponentially increasing drug R&D expenditures by the pharmaceutical industry, in parallel with level or declining new drug approvals, year-by-year, has been a popular talking point at industry meetings and conferences.

Against this backdrop, the pharma industry has evolved dramatically in response to competitive pressures.

  


1990's

2000's

Industry Competitive Environment

Increasing globalization

Emphasis on blockbusters

Globalization

Cost containment

• More emphasis on niche drugs


Pharma Business Model

In-house development

Partner or acquire majority of pipeline

Emerging Companies

Drive toward IPO


Drive toward partnering event

Lean operating model

Emergence from academic research

Drug Discovery Paradigm

Combichem and screen

Structure-based design

Post genomics era - rationale – based discovery

Medicinal Chemistry

Emphasis on pharmacology

Increasing emphasis on druggability and optimizing properties

Chemistry CRO's

Little competition


Intense competition

Continuing growth

Emphasis on cost, skill, and intangibles

 

Drug prices face continued pressure, as the most visible out-of-pocket healthcare expense by most households. This will intensify the incentives driving the use of generic drugs and constrain pricing and use of innovative therapies.

One major area that will continue to be affected by the new sense of cost consciousness is discovery and development.

Diminished margins will only serve to accelerate the move by large pharma and biotech toward M&A and the consequent dismantling of redundant R&D operations. Analyst presentations by these large companies emphasize a goal of outsourcing more than half of the discovery pipeline through collaborations and deal-making with small innovator companies.

These small emerging companies, based on academic inventions and funded by venture capital typically emphasise a lean and flexible business model, using CROs and CMOs for all but their core scientific competencies.

As pricing constraints lead to business models that rein in cost, the use of CROs and CMOs will increase. A recent report predicts that the CRO market will more than double in the five years from 2009 to2014. At the same time, the center of gravity will continue to shift towards providers in the developing world, increasing use of manufacturing sources in emerging markets. The growth of this geographic shift in manufacturing sources will result in cost-saving potential, as well as an enhanced opportunity to penetrate high growth areas.

Our article concludes that this is a time of intense opportunity and growth for chemical synthesis outsourcing CRO's. As a consequence of the pool of talented scientists with former large pharma background, the best CRO's are positioned to become trusted collaborators who not only complete the technical aspects of the projects , but also help guide the program definition and development path.

Staying sharp and flexible, the successful CRO's bring solid infrastructure; highly skilled personnel; advanced knowledge in synthesis, medicinal chemistry, and computational methods; excellent problem solving; and project management skills. In addition, the leading CRO's bring additional services in ADME/Tox, and in vitro and in vivo biological assays.

 

Please use the "contact us" link in the AsisChem web site to request a reprint of the full article.

 

We look forward to meeting you at the fall 2010 ACS National Meeting, in Boston - August 23-26


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Chemistry - The Central Science

May 17, 2010 16:36 by EmileBellott

 

  ... AsisChem has developed a seminar  "Medicinal Chemistry and The Roles of Chemistry in Drug Discovery" to show you how to handle the chemistry in your early-stage drug program.


Chemistry is called "The Central Science"  This name was popularized by a late twentieth century chemistry textbook.  People call it the Central Science because understanding of atoms and molecules is built upon the laws of physics and mathematics.  Biology and life processes represent the next rung up the ladder.  The next higher order of conceptual aggregation is built on an understanding of molecules, their properties, and interactions.

In the discovery and development of small-molecule drugs, chemistry is an essential element, every step of the way.  From target validation - to filing an IND - there are tasks that involve chemistry, chemists, chemical synthesis, and chemical testing.

Last month we were invited to UCSF, along with our partner, Apredica, to give a seminar on Drug Discovery --

 



Our piece "Medicinal Chemistry and The Roles of Chemistry in Drug Discovery" used case studies and examples to show how  chemistry is involved from beginning-to-end.  The talk illustrated some of the important opportunities and pitfalls along the way to advancing a new drug candidate.

The final case study described the (published) development of a new non-nucleoside reverse transcriptase inhibitor ( NNRTI ) at Pfizer-UK.

The path wasn't always linear -- they had to take steps forward and back in order to arrive at the final drug candidate, which is now in clinical trials.  Their progress, in terms of IC50, LogP, and half life are shown in the graph.  The Japanese Proverb says: "Fall seven times, get up eight."  Attendees learned how the development team followed this up-and-down prescription, to meet its objectives:

•Improve Half-life
•Improve potency
•Maintain good side effect profile
•Maintain activity against viral mutation
•Create novel IP
•Easily accessible analogs

Due to the overwhelming positive response, we will make our presentation at other universities, and will also present a webinar in June,  for everybody who couldn't attend in person.


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Medicinal Chemistry, ADMET, and Drug Discovery

April 21, 2010 11:09 by EmileBellott

 

 

 _______________________________________________________________________

The Japanese proverb says "Fall seven times, get up, eight"

This is particularly true in the practice of drug discovery.  As I was preparing for this Friday's seminar, that we will give jointly with Apredica, at UCSF.  I had occasion to review an example of lead-optimization and nomination of a clinical candidate.  This series of three papers, that I choseto discuss as a case study, went from a discontinued clinical compound -to a novel NCE - to clinical candidate.

 ( see: series of papers by Mowbray, et al., Bioorganic & Medicinal Chemistry Letters, 2009 )

On paper, it sounded so easy...  If only they knew in advance, where they would end up.  From the starting point, to the candidate spanned hundreds of compounds, and many man-hours of synthetic and analytical effort.  

All this was done according to a plan that divided the molecule into three zones, for trial of various substituents.  [ Recall that Julius Caesar said that "All Gaul is divided into three parts" ]

LogP got worse, while half life in human liver microsomes got better.  Then the opposite occurred in the next wave.  then back again, as they "fell down" and "got up" many times, in a pitched battle of man vs nature.

In the end, they got it right.  Log P was superbly low.  Half life and predicted clearance were in a good range, and in vitro tox was clean.

 

( Please see our blog entry of January 26, 2010 on Lipinski's Rules, LogP and other Physicochemical properties that affect drug properties and activity. )

 

WE are particularly pleased to inaugurate our seminars at UCSF, the premier US institution of academic drug development.  As we noted in the March 9 Blog entry,  there is increasing interest in academic sources of drug discovery, as the models  for innovation, entrepreneurshipand the industry evolve  in the new decade.

 

 

Hear all about it this Friday, April 23, 2010, at 12:00 in 212 Byers Hall,  at the UCSF Mission Bay campus, San Francisco.

Medicinal Chemistry – The Roles of Chemistry in Drug Discovery(AsisChem- Emile Bellott)
and
Drug-like Properties -- Why early in vitro ADME is Important
(Apredica - Bob Annand )

 

 


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A New Approach To Academic Licensing

April 6, 2010 17:19 by EmileBellott

 

 

 

 

On the next day, we had an opportunity to visit with a colleague at the technology licensing office of a major research university.  I had previously worked with him, when my former companies licensed in  drug candidates for development.

 The timeline from discovery through proof of concept in man, is aptly named the ‘valley of death’, because this part of the program is the most risky element of drug development. In the prevailing view of drug discovery and development, the economic value of a program (pipeline asset) increases over time, as the program is ‘de-risked’. A favorable value proposition sets the stage for monetizing the asset, through licensing, partnering or sale. In the classic large company business model, this would not be a problem, as planned and measured resources are applied to meet specified milestones.

 In a tight capital environment and with industry focus on relatively de-risked programs, the ‘valley of death’ has become a problem for academic innovators. University technology transfer offices have emphasised proactive business development, to appeal to potential interested partners, for licensing and development. They expect to see additional animal data, market projections, and a solid IP position, with freedom to operate.


Major research universities and teaching hospitals have responded strategically, by creating ‘accelerator funds’. These funds award competitive translational grants to principal investigators, to help advance their programme towards its commercial potential. In a typical scenario, the technology office provides mentorship, expert advisors, program planning and other advice, as well as support in contracting and project management activities.

Reflecting the new realities of the competitive environment, selection of candidate programs follows priorities similar to those that an innovator drug company would employ. Projects must show a clear path to market and estimation of commercial potential, if successful.  Universities are attempting to utilise other non-dilutive sources of funds, such as targeted philanthropy and government small business grants, whenever possible in support of the acceleration effort.


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New York March 9 - Venture Capital, New Ventures, and Licensing

April 6, 2010 15:10 by EmileBellott

 

 

 A View From The Top

 

It's always a pleasure to visit Manhattan. The city is awesome.

We had an opportunity to visit several prospective clients and to renew acquaintances with an existing academic client who is starting a new company and wants to work with us on their synthesis – which we pioneered with them. The basis of the company is a license from an academic institution.

Maybe it's fate or kharma, but the underlying theme of the visit was licensing, ventures, and venture capital.

On the 9th, I attended VC Outlook-BIO, a reception and panel discussion in the offices of Goodwin Proctor LLP, in the 23rd floor of the New York Times Building. This panel covered the latest situation briefing on capital and start-ups, with emphasis on the biotech / medical sectors.

As the Wall Street Journal expounded, that very morning, capital continues to be tight. The outlook for emerging companies is challenging, because the total raised by venture capitalists in the US was down substantially due to the realities of the financial markets.

 

 View Inside The Lobby of The New York Times Building

 

In 2009, total VC investments were $17.7Bn, down 31 percent from the year before. Life sciences were somewhat more fortunate – VC investment was down 11 percent year to year. Furthermore, in light of continuing shortfall of capital intake, the VC industry is preserving capital for existing portfolio companies and private equity investments. Early stage deals, while still happening are more difficult. The profile of investments and funds is also shifting towards higher growth locales such as asia.

For start-ups the picture is complicated by the fact that the emphasis is on relatively de-risked opportunities and programs that have a shorter path to market. VC's are more risk averse, today, and frequently invest in start-up companies that are based on programs in-licensed from large pharmas. In-licensed academic technologies may appear less attractive in some cases, because the academic institutions are placing a high expectation on royalty streams.

Large biotech and pharma firms, who are relatively cash-rich are concentrating on later stage programs where there is a proof-of concept. In the larger biotech and pharmaceutical firms, the goal is to externally source up to 50 percent of their discovery pipelines. This provides a ready exit strategy for cash-starved mid and late stage smaller enterprises, for whom the traditional IPO route is not viable in the present and near-term economic climate.

The last and most poignant question is the fate of start-ups. The old axiom that there's always money for a good idea is slim comfort, indeed. On the academic side, large companies are helping nascent programs get through the “valley of death” by increasing investment in academic programs and licensing opportunities.

The panelists emphasized that access to capital for startups will continue to be constrained for the forseeable future. They offered several important criteria for investment opportunities that they would find attractive:


  1. A “disruptive” game changing technology or therapy

  2. The quality of the team

  3. A straightforward value proposition

  4. A clearly delineated path to the market

  5. First in class or best in class therapeutic

  6. Lower technical and operational risk

  7. Lean and efficient business model




 

 

 



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Happy Valentines Day

February 15, 2010 17:19 by EmileBellott

 

 
Valentines day candies brought to mind the story of Professor Ugi and the artificial sweetener that he made in his home laboratory.  I was wondering about the variety of artificial sweeteners that have been discovered -- and how sweet they really are.  Finally, what are their chemical structures ?
 
 
A quick look at Wikipedia provides a list of the most common synthetic chemical sweeteners.  Note that not all of these materials are still approved for human use.  As we have gained a greater knowledge of toxicology and side effects on living organisms, only a few of these are approved for food use -  depending on the country and regulatory authority.
 
 

 
 Mainly, the artificial sweeteners are products of chemical synthesis.  The approved sweeteners  have several characteristics in common:
 
1.  Sweet taste
2.  Non-toxic
3.  Inexpensive to manufacture
4.  Many times sweeter than sugar
 
The last characteristic is important, because natural cane or beet  sugar ( sucrose) is cheap and plentiful in pure form.  It is one of the most widely traded commodities in the world, accounting for over 2 percent of the global dry cargo market.  When I first studied organic chemistry, it was said that Sucrose was the single pure chemical substance produced in the greatest quantity, worldwide.
 
How sweet are these sweeteners ?  They range from 30 x to 8000 x the sweetness of sugar .  See the bar-graph, below.
 

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Don't Try This at Home

February 7, 2010 14:03 by EmileBellott

What are the attributes that lead to success ?  For scientists, artists,  musicians, and athletes, Malcolm Gladwell, in his best-selling book, "Outliers"  observes that in every field of endeavor, outstanding tendencies show up at an early age -- and mastery is built on more than  10,000 hours of experience.

National technological competitiveness has been attributed to  a baby-boom cohort of people who had learned hands-on through  youthful hobbies such as electronics, auto mechanics, other do-it-yourself endeavors. 

Chemistry is the same.  At almost every award ceremony and scientific conference, the presenter regales the audience with tales of  early experiences with home laboratories, explosions, pyrothechics, and smelly chemical experiments in the basement ( and the family doq was lucky to stay safely out of the way).  Just about everyone has heard a story like this.  The story below was related first-hand, from the great chemist, Ivar Ugi, himself...

Professor Ivar Ugi ( 1930-2005 ) was a famous organic chemist, who studied the chemistry of isonitriles; invented the multicomponent condensation reaction known as the Ugi Reaction; and made major contributions to theoretical chemistry.  

Prof. Ugi, who was on the short list for the 1998  nobel prize in chemistry, was the first investigator to use the term "chemical library" to describe the outcome of a combinatorial synthesis scheme.

In his illustrious career, he was the youngest ever, Director of Research at Bayer AG, and subsequently had a highly prolific career in academia, at USC and Technical University of Munich.  

I became acquainted with Prof Ugi in 1995, when he was a consultant for my group at Pharm-Eco Laboratories.

How did he get started in chemistry ?  It was an early interest - in his home laboratory, as a boy.

In the spring of 1996, professor Ugi related the following story to me:

"I got interested in chemistry during the war (WW-II) because I enjoyed games with explosions.  At age 15 I got some little book about chemistry and explosives and read and read .  I found out how one could produce artificial sweeteners by converting a headache medicine.

"Just after the war saccharine was not available  Sugar was not available.  So I read the chemical literature and I found one of these sweetening compounds [ Dulcin] that could be easily made from some pharmaceutical drugs that I could buy.... Some headache pills [Phenacetin].  I learned to convert it into sweetening compounds.

"So the first thing that I was doing in chemistry at home -- and the house was smelly and full of hydrochloric acid, et cetera.  I succeeded in producing these sweeteners, which I was then selling to people."

x

Method for converting the pain medicine, Phenacetin, to the

sweetener, Dulcin, hand written by Prof Ugi, on the back of

an airport parking receipt,  in 1996.

 He made the sweetener and exchanged it for goods and money with his neighbors.  He had read so much chemistry by the time he attended the university of Tübingen, he did not need any additional background and was able to spend almost all of his time doing research in the laboratory.

Prof Ugi, in his office at Technical University of Munich, in 1995 

 

Download Ugi bio:

www.bos06.ttu.ee/files/abstracts/Domling.pdf

 

 


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Bioavailability: The Secret of Success is Just Being There

January 26, 2010 08:12 by EmileBellott

In drug development, bioavailability of a drug in the target tissue is a necessary precondition of the therapeutic benefit. Beyond this, however, it's necessary to consider how the drug can actually get from the bottle – to the desired point of action.

Due to the greater number of patients taking one or more drugs for chronic conditions, it is increasingly imperative to design drugs that can be administered orally. Oral administration is a practical and highly economic mode of therapy, that simplifies the delivery of medical care and improves patient compliance with the intended dosing regimen.

In a drug development program, drug-like properties are designed in at the lead-optimization stage, by synthesis of many analogs, careful observation of their properties, and application of medicina chemistry principles.


 

 

Lipinski's Rules...  How to make a compound that has good oral bioavailability

In a study of thousands of drug compounds, Chris Lipinski, then at Pfizer, observed a regularity in “Drug-Like Properties” of the many compounds that were successfully administered orally – had good oral bioavailability.  In addition to being water soluble, such drugs had properties and attributes that became known as “Lipinski's Rule of Five”, or more commonly, Lipinski's Rules:

Ideal Properties of an Orally available Drug

 Molecular weight -- less than 500 daltons

Octanol/Water partition coefficient, logP – less than 5

No more than 5 Hydrogen-bond donors

No more than 10 Hydrogen-bond acceptors

Rotatable bonds -- less than 1

_____________________________________________

Ref:  C. A. Lipinski, “Drug-Like Properties and The Causes of Poor Solubility and Poor Permeability”, J. Pharmacol. Toxicol. Methods, 44, 235 (2000)

  

As a generalization good water solubility is favored by low molecular weight; low logP; more H-Bond donors and acceptors; and greater charge and/or polarity. Membrane absorption is favored by higher logP; less H-bonding; less charge and polarity, and more flexibility. All of these same factors also have a bearing on metabolism and elimination, as well.

Achieving a drug with favorable oral bioavailability involves a trade off of physicochemical properties in the proposed drug molecule. Hence the general guidelines given above provide guidance as to what has worked in the past in the majority of instances.

The most recent review of these factors concludes that lipophilicity; percent polar surface area; and H-Bond donor count are the most important. Average values have not changed significantly between populations of pre-1983 and post –1983 drug compounds. In contrast, mean values of molecular weight, N+O count; H-Bond acceptor count; rotatable bonds and rings have increased 13 to 29% in the post 1983 drug group.

Properties of marketed oral drugs:


Compound Property

Average of Oral Drugs

1983-2002

Molecular Weight

377

cLogP

2.5

HB Donors

1.77

HB Acceptors

( N+O ) 3.74

Rotatable Bonds

6.42

Polar Surface Area

102.2

Rings

2.88


Ref:  P. D. Leeson and A. M. Davis, “Time-Related Differences in the Physical Property Profiles of Oral Drugs”, J. Med Chem., 47, 6338 (2004)

 


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