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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India

July 14, 2018 2:18 pm / 4 Comments on National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India


times now 1

DR ANTHONY MEVIN CRASTO Conferred prestigious individual national award at function for contribution to Pharma society from Times Network, National Awards for Marketing Excellence ( For Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai India

times now 5

TIMES NOW 2 TIMES NOW 3

times 4

 

 

 

 

 

 

////////////National award,  contribution to Pharma society, Times Network, Excellence in HEALTHCARE,  5th July, 2018, Taj Lands End, Mumbai,  India, ANTHONY CRASTO

#hotpersoninawheelchair
#worlddrugtracker

Sigma-concepts.com a Website for excellent reading with figures & diagrams

November 10, 2016 1:29 am / 1 Comment on Sigma-concepts.com a Website for excellent reading with figures & diagrams


6sigmaconceptsstr0

READ  http://6sigma-concepts.com/

Dr. Amrendra Kumar Roy

Dr. Amrendra Kumar Roy

QbD Head, Jubilant Generics, NOIDA

A Six-sigma and QbD professional

sigma-concepts.com WEBSITE

https://www.facebook.com/6sigmaconcepts/

Resistive Technosource Private Limited

206 II floor Devika Chamber, RDC, Hapur Rd, Block 1, P & T Colony, Raj Nagar, Ghaziabad, Uttar Pradesh 201002
https://twitter.com/6sigmaconcepts
QUOTE………..

OUR VISION

We would like to share our ~13 yrs of practical experience in the field of product development using statistical tools. But first, what compelled us to pursue six-sigma. Most of us started our career as a process chemist after completing PhD and it was during those initial days we realized the importance of “first time right” during commercialization. This enabled not only first mover advantage but also ensured timely and un-interrupted supply of our products into the market. Another aspect of the process development is its robustness, which ensures sustainable margins in whatever products we manufacture. Above achievement was possible only because of the six-sigma tools that we learned and applied at R&D stage. Latter we shifted our focus to the legacy products running in the plants, which we again studied using six-sigma tools to beat the eroding margins and this was possible because of few chemical engineers with six-sigma black belt joined the team.

As a chemist we were never trained on statistical tools hence, it was really a Herculean task for us to understand it. Another problem we faced was the statistical software, we would like to confess that we were never comfortable using these software as we were aware of “garbage in and garbage out” concept very well. We were never confident of the calculations thrown by software because we were not acquainted with the statistics. To site some examples

We were using regression analysis on five variables and found that we were getting an R Sq. of ~0.99 by including all five variables. We were happy about the results but we failed to realize that Adj. R Sq. has decreased while we added 4th and 5th variable, ending with a regression equation with un-necessary terms in it. As a result, we un-necessarily proposed control strategies for those insignificant variables which involved investment.

Another mistake we often made is to ignore the outliers during the Design of Experiments (DOE)! But we always wonder why we were ignoring these outliers? Just because we wanted to have a good regression equation? Are we not doubting our own experimental data? Later on we learned that if we keep ignoring the outliers just to have a good model, we would ultimately be modeling the system noise rather than modeling the effect. It is better to investigate the cause of outlier rather than ignoring it.

Above examples made us realize that having theoretical knowledge of six-sigma is not enough, it is the practical experience that really matters. Real challenge is the correct analysis of the experiments data so that the product could be scaled up without any problem. Learning to do the correct statistical analysis using any software was the mantra of the game. We should be confident that whatever output we are getting from the software is correct and this is possible only if we have good understanding of the statistical concepts. We are not saying that we should master the statistics but we must have clear understanding of the concepts before we use any software. It took us too long to understand these fundamentals aspects of applied statistics, main reason being the absence of statistical guru with adequate industrial experience. But major hurdle was to find a good tutor or at least a good book which can explain the concepts without involving too much of the statistics. We started looking for applied statistics courses and we found some solace in the “research methodology” module of MBA courses. Having gone through it, it gave us the confidence that six sigma tools can be learned without having in-depth knowledge of statistics.

During last 7-8 years we developed our own way of learning applied statistics with the help of diagrams and figures. During this journey we also found that each statistical topic have some connections with other topics and we can’t study any topic in isolation.

How normal distribution and hypothesis testing is working behind the scene in ANOVA, DoE, regression analysis and control charts. 

Having gone through these hardship, I decided to share the experience with all those who like to understand the six sigma tools but are reluctant in doing so because of the statistics involved. Our website would help all six-sigma aspirants to understand the statistical concepts with the help of figures and diagrams. We would also be helping you in understanding the relationship between two unrelated topics like hypothesis testing and control charts.

Another feature that will help you is the solved example from the industry. Hence this would be an ideal website if you wish to appear for green/black belt exam from a reputed institute. We are saying this because we ourselves are ASQ certified six-sigma black belt and we want to share one important thing about the exam that we experienced, you can’t clear the exam unless you have understood the statistical concepts behind every six sigma tools. When we are saying understanding the statistical concepts, it doesn’t means learning pure statistics but only the concepts behind any tool, their advantages and limitations. This becomes important as ASQ never asks direct questions but questions are applied in nature. For example

A bulb production process found to follow normal distribution. A sample of 100 bulbs were drawn from a batch of 1000000 at random and found to have a mean life time of 1525 hrs. Historical mean life time was found to be 1548 hrs. with a standard deviation of 200 hrs. What is the percentage of bulbs having a life span of exactly 1548 hrs. from the current batch?

A manufacturing process was under optimization in a plant and a sample to 10 bags were selected at random from each batch. There were 5 batches in total and the mean weight (in Kgs) of the samples (10 bags) withdrawn are 100.5, 101.1, 99.8, 100.2 and 99.95. The range (in Kg) for these consecutive 5 batches were found to be 0.7, 0.9, 0.8, 0.9 and 1 Kg. Calculate the control limits for the  chart.

Problem looks simple, in first case just calculate the z-value to tell the percentage and in the second case appears to be a direct question where we can easily calculate the control limits. But there is a catch, in first case probability for z = any number is zero! it is always about finding the probability between two numbers for a continuous probability distribution. In second case, if you missed the opening statement “under optimization” you are wasting your time in calculating the control limits, as control charts are always calculated for the stable process. In either of the question if you start the calculation, we can ensure that you won’t be finishing the exam in time!

Another major issue during applying six-sigma is the “use of right tool at the right place”. Hence our focus would not only to understand the concepts behind any statistical tools but also about selecting an appropriate tool for a given situation.

This website will start posting the six sigma topics (mainly statistical portion) from first week of January, 2017. Hence get registered on this course as soon as possible. The way we are planning to run the course is by posting one topic every week so that we can understand it well before taking subsequent topic. We are doing it in a slow pace because once we are on some advanced topic say “normal distribution” then at that time we should not be struggling with topics like variance, mean, z-transformation etc. Each topic will be followed by real life examples so that one can understand not only the concepts but also the use of appropriate tools. At the end of each topic we will also be demonstrating the use of excel sheet in resolving statistical problems. We are emphasizing on excel sheet as it is available to all. This would be our main USP during the course.

UNQUOTE………

//////////QBD, 6sigma-concepts.com, AMRENDRA ROY

Register Today for the ACS Symposium in India on Recent Advances in Drug Development, 11-12 November 2016 in Hyderabad, India

October 14, 2016 7:08 am / Leave a comment


acs

cas

Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India

Recent Advances in Drug Development

Register Today for the ACS Symposium in India on Recent Advances in Drug Development

To view this email as a web page, go here.

Register now for the inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India. Be sure to secure your seat today as rates will increase on 27 October!

http://acssymposium.org.in/
The theme of the Symposium is Recent Advances in Drug Development. The event will feature lectures by the world’s leading researchers and experts in the pharma industry, including:

  • Dr. Peter Senter of Seattle Genetics
  • Dr. Jagath Reddy Junutula of Cellerant Therapeutics, Inc.
  • Dr. Ming-Wei Wang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences

This is an exclusive event being organized in partnership with Dr. Reddy’s Laboratories for pharma professionals throughout India. Space is limited so register today!

Please visit our website to learn more about the speakers and the program.

Register today to ensure your access to the ACS Industry Symposium. We look forward to seeing you in Hyderabad in November.

CAS
2540 Olentangy River Rd Columbus, OH 43202 US

cas

http://acssymposium.org.in/

CAS
2540 Olentangy River Rd Columbus, OH 43202 US

cas

http://acssymposium.org.in/

 

 

Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India
Recent Advances in Drug Development

/////// ACS Symposium, Recent Advances in Drug Development, 11-12 November 2016, Hyderabad, India, dr reddys, cas

CDMO Ash Stevens to Be Acquired by Piramal Enterprises

August 17, 2016 3:36 am / Leave a comment


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Piramal Enterprises Limited announced that its wholly owned subsidiary in the U.S. has entered into an agreement to acquire 100 percent stake in Ash Stevens Inc., a U.S.-based contract development and manufacturing organization (CDMO), in an all cash deal for a consideration of USD $42.95 million plus an earn-out consideration capped at $10 million. This potential transaction is expected to be completed by the end of August.

Located in Riverview, Michigan, Ash Stevens has over 50 years of experience in contract manufacturing, and serves several biotech, mid-size pharma, and large pharmaceutical clients worldwide.

With over 60,000 sq. ft. of facilities, eight chemical drug development and production laboratories, and six full-scale production areas, Ash Stevens has built a stellar reputation, led by science, driven by operational excellence, and one that emphasizes quality as a culture. As one of the leaders in HPAPI manufacture, Ash Stevens has an impeccable safety record of working with high potency anti-cancer agents and other highly-potent therapeutics. The state-of-the-art manufacturing facility in Michigan features all necessary engineering and containment controls for the safe handling and cGMP manufacture of small and large-scale HPAPIs, with Occupational Exposure Limits (OELs) ≤ 0.1µg/m3. The facility has approvals from U.S., EU, Australia, Japan, Korea, and Mexico regulatory agencies.

“The acquisition of Ash Stevens fits well with our strategy to build an asset platform that offers value to our partners and collaborators. Currently, around 25 percent of the molecules in clinical development are potent. Our clients are looking for reliable partners that can assist them in advancing these programs forward,” said Vivek Sharma, CEO of Piramal Pharma Solutions. He further adds, “North America is a key market that we can now service with our three local facilities – the Coldstream Labs in Kentucky for fill finish needs, the Torcan facility in Toronto for complex high value APIs and now, Ash Stevens in Michigan for HPAPIs. Having facilities with a differentiated platform and geographical proximity to clients are keys towards building strategic partnerships. We expect this acquisition to also be synergistic with our Antibody Drug Conjugates (ADCs) and injectable business. We can now fulfill client requirements for a single source of supply for both high potent APIs and drug products.”

“With its rich history of scientific excellence, a track record of 12 product launches, Ash Stevens is well poised to become the partner of choice for clients looking to advance programs from early development through launch. In addition to the business benefits that the combined entity will bring to our clients, I am also pleased that the firms share common core values: both were founded by successful entrepreneurs, value integrity, and are committed to a customer-first approach,” said Dr. Mark Cassidy, President of the API Business at Piramal Pharma Solutions. “I am pleased to welcome the Ash Stevens team into the Piramal group. We expect them to be an integral part of our future growth plans.”

Added Dr. Stephen Munk, CEO of Ash Stevens, “We look forward to working with the Piramal leadership and management team, to develop API solutions that benefit customers and improve the lives of patients. The commitment that Piramal has shown towards growing its healthcare businesses, coupled with the complementary capabilities that our two firms have, makes this an exciting time for Ash Stevens and our employees. We have already identified areas where we can create significant value together, and will be moving forward rapidly to achieve those objectives.”

The transaction is not subject to any regulatory approvals. No related party of PEL has any interest in Ash Stevens.

Wells Fargo Securities, LLC served as exclusive financial advisor to Ash Stevens, with legal counsel provided by Morrison & Foerster LLP.

For further information on the financials, please visit our website: www.piramal.com.

Dr. Stephen A. Munk, President and CEO of Ash Stevens Inc.
Large scale reactor train with 2000, 3000, and 4000 L glass-lined reactors equipped with split butterfly valves.
Ash Stevens’ down draft kilo suite with low temperature capability.

Ajay Piramal

The Piramal family's purposeful philanthropy

From left: Anand Piramal, executive director, Piramal Group; Swati Piramal, vice-chairperson, Piramal Group; Ajay Piramal, chairman, Piramal Group; Nandini Piramal, executive director, Piramal Enterprises; and Peter DeYoung, president, Piramal Enterprises

////////////CDMO,  Ash Stevens, Piramal Enterprises, Stephen A. Munk

Scaling up from mg to Kgs – Making your First GMP Batch

August 3, 2016 11:12 am / Leave a comment


STR1

Scaling up from mg to Kgs – Making your First GMP Batch 

6th – 7th October 2016, Clearwater, USA

“the course was very informative and it allowed me to see the big picture from discovery stage to pilot plant” 
Genentech

Course Outline:

  • Introduction
  • Making the first 100g non-GMP Batch
  • Non-GMP vs GMP preparation
  • Physical version and form
  • Process safety and raw materials supply
  • Scaling into fixed vessels
  • Technology transfer
  • Genotoxic impurities
  • Case studies and Review

Who should attend:

  • Project managers
  • Project leaders
  • Bench chemists
  • New starters
  • MedChem Support teams

This course aims to provide attendees with a good understanding of the issues involved taking development candidates to the first in human trials.

Click here to Download the Course Brochure

Presented by Dr John Knight, JKonsult Ltd

John Knight

Managing Director at JKONSULT Ltd

STR1
Click here to Download the Course Brochure

“Brilliant Course, learn lots of tips and tricks”
Vertex
“First incursion into Chemical Development has been very, very educational. John’s way of explaining the material has been wonderful.”
Almirall

“Very clear and interesting sessions with a lot of relevant examples and not only theory.” 
Oribase Pharma
LINK
LITERATURE FROM INTERNET ON HIS TOPIC
//////////Scaling up,  mg to Kgs, Making,  First GMP Batch, SCIENTIFIC UPDATE,  JOHN KNIGHT, Clearwater, USA

USFDA approves Indoco’s Allopurinol ANDA

August 3, 2016 11:09 am / Leave a comment


usfda-approval-Allopurinol-forprint.jpg

Indoco Remedies Ltd.

Indoco Remedies Limited (India) | Facebook

https://www.facebook.com/Indoco-Remedies-Limited-India-317944458228011/

USFDA approves Indoco’s Allopurinol ANDA… Indoco Remedies Limited (India)’s … Indoco Remedies Limited (India) added a new photo

Allopurinol 3d structure.png

Allopurinol, sold under the brand name Zyloprim and generics, is a medication used primarily to treat excess uric acid in the bloodand its complications, including chronic gout. It is a xanthine oxidase inhibitor and is administered orally.

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.

Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name Zyloprim. Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is now a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron

Aditi Kare Panandikar, Managing Director, Indoco Remedies

click above

Aditi Kare Panandikar gets award

///////////Indoco Remedies Ltd, USFDA,  approves,  Indoco’s,  Allopurinol,  ANDA, Aditi Kare Panandikar, Managing Director,

Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages

July 15, 2016 10:48 am / 1 Comment on Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages


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Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability  to  design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.

Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………

INTRODUCTION

Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.

The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.

They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or  by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes

Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands,  heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks.  They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.

Some of the compounds prepared by Sreeni labs;

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See presentation below

LINK ON SLIDESHARE

Sreeni Labs Profile from Sreenivasa Reddy

Managing Director at Sreeni Labs Private Limited\

 

Few Case Studies : Source SEEENI LABS

QUOTE………….

One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.

 

One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.

 

One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.

 

One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.

 

Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers.  We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.

 

One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO  for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide,  palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route  in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.

 

One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.  

UNQUOTE…………

 

The man behind Seeni labs is Dr. Sreenivasa Reddy Mundla 

Sreenivasa Reddy

Dr. Sreenivasa Reddy Mundla.

Managing Director at Sreeni Labs Private Limited

Sreeni Labs Private Limited

Road No:12, Plot No:24,25,26

  • IDA, Nacharam
    Hyderabad, 500076
    Telangana State, India

Links

LINKEDIN https://in.linkedin.com/in/sreenivasa-reddy-10b5876

FACEBOOK https://www.facebook.com/sreenivasa.mundla

RESEARCHGATE https://www.researchgate.net/profile/Sreenivasa_Mundla/info

EMAIL mundlasr@hotmail.com,  Info@sreenilabs.com, Sreeni@sreenilabs.com

Dr. Sreenivasa  Reddy Mundla

Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000,  worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis. 

In 2007  resigned to his  job and founded Sreeni Labs based in Hyderabad, Telangana, India  and started working with various global customers and solving various challenging synthesis problems. 
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale. 

They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects

Experience

Founder & Managing Director

Sreeni Labs Private Limited

August 2007 – Present (8 years 11 months)

Sreeni Labs Profile

Sreeni Labs Profile

View On SlideShare

Principal Research Scientist

Eli Lilly and Company

March 2001 – August 2007 (6 years 6 months)

Senior Research Scientist

Procter & Gamble

July 1994 – February 2001 (6 years 8 months)

Education

University of Hyderabad

Doctor of Philosophy (Ph.D.), 
1986 – 1992

With Sreenivasa Mundla, Narahara sastry, Ram Kishan Rao, Jagadeesh Bharatam, Jagadish Gunjur and Jagadish Bharatham.

 

PUBLICATIONS

Article: Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak

Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative

Sreenivasa Mundla

Aug 2010 · ChemInform

Article: Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss

Apr 2008 · Journal of Medicinal Chemistry

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Feb 2008 · ChemInform

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Nov 2007 · Tetrahedron

Article: Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling

Apr 2006 · Journal of Medicinal Chemistry

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Article: Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system

Hui Cao · Sreenivasa R. Mundla · James M. Cook

Aug 2003 · Tetrahedron Letters

Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes

Sreenivasa R. Mundla

Nov 2000 · ChemInform

Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

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Patents by Inventor Dr.Sreenivasa Reddy Mundla

  • TGF-? inhibitors

    Patent number: 7872020

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Grant

    Filed: June 29, 2006

    Date of Patent: January 18, 2011

    Assignee: Eli Lilly and Company

    Inventor: Sreenivasa Reddy Mundla

  • TGF-BETA INHIBITORS

    Publication number: 20100120854

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Application

    Filed: June 29, 2006

    Publication date: May 13, 2010

    Applicant: ELI LILLY AND COMPANY

    Inventor: Sreenivasa Reddy Mundla

  • Process for making 2-amino-2-imidazoline, guanidine and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives

    Patent number: 6066740

    Abstract: The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.

    Type: Grant

    Filed: November 25, 1997

    Date of Patent: May 23, 2000

    Assignee: The Procter & Gamble Company

    Inventors: Michael Selden Godlewski, Sean Rees Klopfenstein, Sreenivasa Reddy Mundla, William Lee Seibel, Randy Stuart Muth

TGF-β inhibitors

US 7872020 B2

Sreenivasa Reddy Mundla

The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.

Figure US07872020-20110118-C00002

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Figure US07872020-20110118-C00008

Galunisertib

1H NMR (CDCl3): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16

ABOVE MOLECULE IS

https://newdrugapprovals.org/2016/05/04/galunisertib/

Galunisertib

Phase III

LY-2157299

CAS No.700874-72-2

 

 

READ MY PRESENTATION ON

Accelerating Generic Approvals, see how you can accelerate your drug development programme

Accelerating Generic Approvals by Dr Anthony Crasto

KEYWORDS   Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India,  new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3,  API, drugs, medicines

Cipla to invest in South Africa’s first biosimilars production facility

July 14, 2016 10:17 am / Leave a comment


Cipla to invest in South Africa’s first biosimilars production facility
Indian-based pharmaceutical and biotechnology company Cipla will invest more than R1.3bn ($19.34m) in the first advanced biotech manufacturing facility in South Africa for the production of biosimilars.

Indian-based pharmaceutical and biotechnology company Cipla will invest more than R1.3bn ($19.34m) in the first advanced biotech manufacturing facility in South Africa for the production of biosimilars.

The investment will be carried out by South African subsidiary Cipla BioTec…………………cont

read at

http://www.pharmaceutical-technology.com/news/newscipla-invest-south-africas-first-biosimilars-production-facility-4945516?WT.mc_id=DN_News

Cipla Managing director and global CEO Subhanu Saxena

 

Dr Y.K. Hamied,

Department of Trade and Industries Special Economic Zone of Dube Tradeport, DURBAN, SOUTHAFRICA

 

///Cipla, South Africa, biosimilars,  production facility, Dube Tradeport, Cipla BioTec Pvt Ltd, Durban, SOUTHAFRICA

CRD 1152, CURADEV PHARMA PRIVATE LTD

April 5, 2016 10:34 am / Leave a comment


Several candidates….one is…….CRD1152

ONE OF THEM IS CRD 1152

Kynurenine pathway regulators (solid tumors)

Compound 2

CAS1638121-21-7

US159738837

N3-(3-Chloro-4- fluorophenyl) furo[2,3- c]pyridine-2,3- diamine

COMPD 190

CAS 1638118-99-6

US159738837

COMPD248

US159738837

7-Chloro-N3- (3-chloro-4- fluorophenyl) furo[2,3- c]pyridine-2,3- diamine,  166

DMSO-d6: δ 7.87 (d, J = 5.1 Hz, 1H), 7.25 (s, 2H), 7.16-7.10 (m, 2H), 6.88 (d, J = 5.1 Hz, 1H), 6.59 (dd, J′ = 6.2 Hz, J″ = 2.6 Hz, 1H), 6.48 (dt, J′ = 8.8 Hz, J″ = 6.7 Hz, J′′′ = 3.4 Hz, 1H) M + H] 312

US159738837

OR

N3-(3,4- difluorophenyl)- 7-(pyridin-4- yl)furo[2,3- c]pyridine-2,3- diamine, 184

CD3CN: δ 8.72 (s, 2H), 8.26 (s, 3H), 7.07-7.03 (m, 2H), 6.47-6.40 (m, 2H), 5.74 (s, 1H), 5.55 (s, 2H) M + H] 339

US159738837

OR

COMPD73

CAS 1638117-85-7

US159738837

Several candidates………..CRD1152

67

66

Company Curadev Pharma Pvt. Ltd.
Description Small molecule dual indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO1; IDO) inhibitor
Molecular Target Indoleamine 2,3-dioxygenase (INDO) (IDO) ; Tryptophan 2,3-dioxygenase (TDO2) (TDO)
Mechanism of Action Indoleamine 2,3-dioxygenase (INDO) inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Preclinical
Standard Indication Cancer (unspecified)
Indication Details Treat cancer
Regulatory Designation
Partner Roche

Hoffmann-La Roche partners with Curadev Pharma Ltd. for IDO1 and TDO inhibitors (April 20, 2015)

Curadev Pharma Pvt Ltd., founded in 2010 and headquartered in New Delhi, announced that it has entered into a research collaboration and exclusive license agreement with Roche for the development and commercialization of IDO1 and TDO inhibitors to treat cancer. The agreement covers the development of CRD1152, the lead preclinical immune tolerance inhibitor and a research collaboration with Roche’s research and early development organization to further explore the IDO and TDO pathways.

IDO1 (indoleamine-2,3-dioxygenase-1) and TDO (tryptophan-2,3-dioxygenase) are enzymes that mediate cancer-induced immune suppression. This mechanism is exploited by tumor cells as well as certain type of immune cells, limiting the anti-tumor immune response. Dual inhibition of the IDO1 and TDO pathways promises to maintain the immune response, prevent local tumor immune escape and potentially avoid resistance to other immunotherapies when used in combination, and could lead to new treatment options for cancer patients. Curadev’s preclinical lead-compound, a small-molecule that shows potent inhibition of the two rate-limiting enzymes in the tryptophan to kynurenine metabolic pathways, has the potential for mono therapy as well as combination with Roche’s broad oncology pipeline and portfolio.

Under the terms of agreement, which includes a research collaboration with Roche’s research and early development organization, Curadev will receive an upfront payment of $25 million and will be eligible to receive up to $530 million in milestone payments, as well as escalating royalties potentially reaching double digits for the first product from the collaboration developed and commercialized by Roche. Curadev is also eligible for milestones and royalties on any additional products resulting from the research collaboration.

Curadev Announces Research Collaboration and Licensing Agreement to Develop Cancer Immunotherapeutic

Curadev’s dual IDO and TDO immune tolerance inhibitor – a novel approach in cancer immunotherapy

Apr 20, 2015, 06:30 ET from Curadev

NEW DELHI, India, April 20, 2015 /PRNewswire/ —

Curadev Pharma Private Ltd. today announced that it has entered into a research collaboration and exclusive license agreement with Roche for the development and commercialization of IDO1 and TDO inhibitors. The agreement covers the development of the lead preclinical immune tolerance inhibitor and a research collaboration with Roche’s research and early development organization to further explore the IDO and TDO pathways.

IDO1 (indoleamine-2, 3-dioxygenase-1) and TDO (tryptophan-2, 3-dioxygenase) are enzymes that mediate cancer-induced immune suppression. This mechanism is exploited by tumor cells as well as certain type of immune cells, limiting the anti-tumor immune response.

Dual inhibition of the IDO1 and TDO pathways promises to maintain the immune response, prevent local tumor immune escape and potentially avoid resistance to other immunotherapies when used in combination, and could lead to new treatment options for cancer patients. Curadev’s preclinical lead-compound, a small-molecule that shows potent inhibition of the two rate-limiting enzymes in the tryptophan – to kynurenine metabolic pathways, has the potential for mono therapy as well as combination with Roche’s broad oncology pipeline and portfolio.

“We are very excited to be working with the global leader in oncology with their unrivalled expertise in clinical development,” said Arjun Surya, PhD, Chief Scientific Officer, Curadev. “The collaboration acknowledges our focused research efforts on patient-critical drug targets that have yielded a drug candidate that could make a significant difference in the development of novel treatments for patients suffering from cancer.”

Under the terms of agreement, which includes a research collaboration with Roche’s research and early development organization to further extend Curadev’s findings, Curadev will receive an upfront payment of $25 million and will be eligible to receive up to $530 million in milestone payments based on achievement of certain predetermined events and sales levels as well as escalating royalties potentially reaching double digits for the first product from the collaboration developed and commercialized by Roche. Curadev would also be eligible for milestones and royalties on any additional products resulting from the research collaboration. Roche will fund future research, development, manufacturing and commercialization costs and will also provide additional research funding to Curadev for support of the research collaboration.

About Curadev

Headquartered in New Delhi, India, Curadev Pharma Private Limited was founded in 2010 by a team of professionals from the pharmaceutical and biotech sectors with the mission to improve human health and enhance the quality of human life by accelerating the discovery and delivery of new drugs. Curadev focuses on the creation and out-licensing of pre-IND assets and IND packages for drug development.

For further information:

Curadev Partnering

Manish Tandon – VP and Chief Financial Officer, manish@curadev.in

PATENT

US20160046596) INHIBITORS OF THE KYNURENINE PATHWAY

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159738837&recNum=2&maxRec=17&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28curadev%29&tab=PCTDescription

Monali Banerjee
Sandip Middya
Ritesh Shrivastava
Sushil Raina
Arjun Surya
Dharmendra B. Yadav
Veejendra K. Yadav
Kamal Kishore Kapoor
Aranapakam Venkatesan
Roger A. Smith
Scott K. Thompson

ONE ………….Example 2

Synthesis of N3-(3-Chloro-4-fluoro-phenyl)-furo[2,3-c]pyridine-2,3-diamine (Compound 2)

Step 1: 3-Methoxymethoxy-pyridine
      To a stirred solution of 3-hydroxypyridine (60 g, 662.9 mmol) in THF:DMF (120:280 mL) at 0° C. was added t-BuOK (81.8 gm, 729.28 mmol) portion-wise. After stirring the reaction mixture for 15 min, methoxymethyl chloride (52 mL, 696.13 mmol) was added to it at 0° C. and the resulting mixture was stirred for 1 hr at 25° C. Reaction mixture was diluted with water and extracted with ethyl acetate (4×500 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 100 g crude which was purified by column chromatography using silica (100-200 mesh) and 10% EtOAc-hexane as eluent to afford 3-methoxymethoxy-pyridine (54 g) as pale brown liquid. LCMS: 140 (M+H).

Step 2: 3-Methoxymethoxy-pyridine-4-carbaldehyde
      To a stirred solution of 3-methoxymethoxypyridine (2 g, 14.3885 mmol) in anhydrous THF (40 mL) was added TMEDA (1.83 g, 15.82 mmol) at 25° C. The reaction mixture was cooled to −78° C., n-BuLi (7.3 mL, 15.82 mmol, 2.17 M in hexane) was added dropwise manner maintaining the temperature −78° C. After stirring for 2 hr at −78° C., DMF (1.52 g, 20.86 mmol) was added to it and stirred for 2 hr at 25° C. Reaction mixture was cooled to −40° C. and saturated ammonium chloride solution was added drop wise. The reaction mass was extracted with ethyl acetate (250 mL×2), EtOAc part was washed with water followed by brine, dried over sodium sulfate and concentrated under reduced pressure to afford 3 g of crude product which was passed through a pad of silica (100-200 mesh) using 10% EtOAc-hexane as eluent to afford 1.6 g of 3-methoxymethoxy-pyridine-4-carbaldehyde as pale yellow liquid. GC-MS: 167 (m/z).

Step 3: 3-Hydroxy-pyridine-4-carbaldehyde
      To a stirred solution of 3-methoxymethoxypyridine-4-carbaldehyde (11 g, 65.83 mmol) in THF (50 mL) was added 3N HCl (100 mL) and stirred at 60° C. for 1 hr. The reaction mixture was cooled under ice bath and pH was adjusted to 7 with solid K2CO3. Resulting mixture was extracted with EtOAc (250 mL×5). The organic layer was dried over sodium sulfate, concentrated under reduced pressure to afford 15 g of crude which was purified by column chromatography using silica gel (100-200 mesh) and 23% EtOAc/hexane as eluent to afford 4 g of 3-hydroxy-pyridine-4-carbaldehyde as pale yellow solid. GC-MS: 123 (m/z), 1H-NMR (DMSO-d6, 400 MHz): δ 11.04 (bs, 1H), 10.37 (s, 1H), 8.46 (s, 1H), 8.20 (d, 1H, J=4.88 Hz), 7.46 (d, 1H, J=4.88 Hz). GC-FID: 99.51%.

Step 4: 4-{[3-Chloro-4-fluoro-phenylimino]-methyl}-pyridin-3-ol
      3-Hydroxypyridine-4-carbaldehyde (3 g, 24.39 mmol) was taken in mixed solvent (TFE (20 mL):MeCN (20 mL)) and 4-fluoro-3-chloroaniline (3.55 g, 24.39 mmol) was added to it at 25° C. The resulting mixture was stirred at this temperature for 1 hr. The reaction mass was concentrated and purified by triturating with n-pentane to afford 6 g of 4-{[3-chloro-4-fluoro-phenylimino]-methyl}-pyridin-3-ol). LCMS: 251.2 (M+H).

Step 5: N3-(3-Chloro-4-fluoro-phenyl)-furo[2,3-c]pyridine-2,3-diamine
      To a stirred solution of 4-{[3-chloro-4-fluoro-phenylimino]-methyl}-pyridin-3-ol (6 g, 24 mmol) in mixed solvent [DCM (10 mL):TFE (10 mL)] was added TMSCN (10.5 mL, 84 mmol) at 25° C. The reaction mixture was stirred 3 hr at 25° C., concentrated, and the crude material was triturated with n-pentane to provide 4.9 g (73% yield) of N3-(3-chloro-4-fluoro-phenyl)-furo[2,3-c]pyridine-2,3-diamine as pale pink solid. LCMS: 278 (M+H), HPLC: 98.65%, 1H-NMR (DMSO-d6, 400 MHz): δ 8.41 (s, 1H), 8.06 (d, 1H, J=5.08 Hz), 7.14-7.10 (m, 2H), 6.91 (s, 2H), 6.86 (d, 1H, J=5.08 Hz), 6.56-6.54 (m, 1H), 6.48-6.45 (m, 1H).

Monali Banerjee – Director, R&D

Ms. Banerjee has more than 10 years of research experience, during which she has held positions of increasing responsibility. Her past organizations include TCG Lifesciences (Chembiotek) and Sphaera Pharma. Ms. Banerjee is a versatile scientist with a deep understanding of the fundamental issues that underlie various aspects of drug discovery. At Curadev, she has been responsible for target selection, patent analysis, pharmacophore design, assay development, ADME/PK and in vivo and in vitro pharmacology. Ms. Banerjee holds a Masters in Biochemistry and a Bachelors in Chemistry both from Kolkata University.

writeup

The essential amino acid Tryptophan (Trp) is catabolized through the kynurenine (KYN) pathway. The initial rate-limiting step in the kynurenine pathway is performed by heme-containing oxidoreductase enzymes, including tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase-1 (IDO1), and indoleamine 2,3-dioxygenase-2 (IDO2). IDO1 and IDO2 share very limited homology with TDO at the amino acid level and, despite having different molecular structures, each enzyme has the same biochemical activity in that they each catalyze tryptophan to form N-formylkynurenine. IDO1, IDO2, and/or TDO activity alter local tryptophan concentrations, and the build-up of kynurenine pathway metabolites due to the activity of these enzymes can lead to numerous conditions associated with immune suppression.
      IDO1 and TDO are implicated in the maintenance of immunosuppressive conditions associated with the persistence of tumor resistance, chronic infection, HIV infection, malaria, schizophrenia, depression as well as in the normal phenomenon of increased immunological tolerance to prevent fetal rejection in utero. Therapeutic agents that inhibit IDO1, IDO2, and TDO activity can be used to modulate regulatory T cells and activate cytotoxic T cells in immunosuppressive conditions associated with cancer and viral infection (e.g. HIV-AIDS, HCV). The local immunosuppressive properties of the kynurenine pathway and specifically IDO1 and TDO have been implicated in cancer. A large proportion of primary cancer cells have been shown to overexpress IDO1. In addition, TDO has recently been implicated in human brain tumors.
      The earliest experiments had proposed an anti-microbial role for IDO1, and suggested that localized depletion of tryptophan by IDO1 led to microbial death (Yoshida et al., Proc. Natl. Acad. Sci. USA, 1978, 75(8):3998-4000). Subsequent research led to the discovery of a more complex role for IDO1 in immune suppression, best exemplified in the case of maternal tolerance towards the allogeneic fetus where IDO1 plays an immunosuppressive role in preventing fetal rejection from the uterus. Pregnant mice dosed with a specific IDO1 inhibitor rapidly reject allogeneic fetuses through induction of T cells (Munn et al., Science, 1998, 281(5380): 1191-3). Studies since then have established IDO1 as a regulator of certain disorders of the immune system and have discovered that it plays a role in the ability of transplanted tissues to survive in new hosts (Radu et al., Plast. Reconstr. Surg., 2007 June, 119(7):2023-8). It is believed that increased IDO1 activity resulting in elevated kynurenine pathway metabolites causes peripheral and ultimately, systemic immune tolerance. In-vitro studies suggest that the proliferation and function of lymphocytes are exquisitely sensitive to kynurenines (Fallarino et al., Cell Death and Differentiation, 2002, 9(10):1069-1077). The expression of IDO1 by activated dendritic cells suppresses immune response by mechanisms that include inducing cell cycle arrest in T lymphocytes, down regulation of the T lymphocyte cell receptor (TCR) and activation of regulatory T cells (T-regs) (Terness et al., J. Exp. Med., 2002, 196(4):447-457; Fallarino et al., J. Immunol., 2006, 176(11):6752-6761).
      IDO1 is induced chronically by HIV infection and in turn increases regulatory T cells leading to immunosuppression in patients (Sci. Transl. Med., 2010; 2). It has been recently shown that IDO1 inhibition can enhance the level of virus specific T cells and concomitantly reduce the number of virus infected macrophages in a mouse model of HIV (Potula et al., 2005, Blood, 106(7):2382-2390). IDO1 activity has also been implicated in other parasitic infections. Elevated activity of IDO1 in mouse malaria models has also been shown to be abolished by in vivo IDO1 inhibition (Tetsutani K., et al., Parasitology. 2007 7:923-30.
      More recently, numerous reports published by a number of different groups have focused on the ability of tumors to create a tolerogenic environment suitable for survival, growth and metastasis by activating IDO1 (Prendergast, Nature, 2011, 478(7368):192-4). Studies of tumor resistance have shown that cells expressing IDO1 can increase the number of regulatory T cells and suppress cytotoxic T cell responses thus allowing immune escape and promoting tumor tolerance.
      Kynurenine pathway and IDO1 are also believed to play a role in maternal tolerance and immunosuppressive process to prevent fetal rejection in utero (Munn et al., Science, 1998, 281(5380):1191-1193). Pregnant mice dosed with a specific IDO1 inhibitor rapidly reject allogeneic fetuses through suppression of T cells activity (Munn et al., Science, 1998, 281(5380):1191-1193). Studies since then have established IDO1 as a regulator of immune-mediated disorders and suggest that it plays a role in the ability of transplanted tissues to survive in new hosts (Radu et al., Plast. Reconstr. Surg., 2007 June, 119(7):2023-8).
      The local immunosuppressive properties of the kynurenine pathway and specifically IDO1 and TDO have been implicated in cancer. A large proportion of primary cancer cells overexpress IDO1 and/or TDO (Pilotte et al., Proc. Natl. Acad. Sci. USA, 2012, Vol. 109(7):2497-2502). Several studies have focused on the ability of tumors to create a tolerogenic environment suitable for survival, growth and metastasis by activating IDO1 (Prendergast, Nature, 2011, 478:192-4). Increase in the number of T-regs and suppression of cytotoxic T cell responses associated with dysregulation of the Kynurenine pathway by overexpression of IDO1 and/or TDO appears to result in tumor resistance and promote tumor tolerance.
      Data from both clinical and animal studies suggest that inhibiting IDO1 and/or TDO activity could be beneficial for cancer patients and may slow or prevent tumor metastases (Muller et al., Nature Medicine, 2005, 11(3):312-319; Brody et al., Cell Cycle, 2009, 8(12):1930-1934; Witkiewicz et al., Journal of the American College of Surgeons, 2008, 206:849-854; Pilotte et al., Proc. Natl. Acad. Sci. USA, 2012, Vol. 109(7):2497-2502). Genetic ablation of the IDO1 gene in mice (IDO1−/−) resulted in decreased incidence of DMBA-induced premalignant skin papillomas (Muller et al., PNAS, 2008, 105(44):17073-17078). Silencing of IDO1 expression by siRNA or a pharmacological IDO1 inhibitor 1-methyl tryptophan enhanced tumor-specific killing (Clin. Cancer Res., 2009, 15(2). In addition, inhibiting IDO1 in tumor-bearing hosts improved the outcome of conventional chemotherapy at reduced doses (Clin. Cancer Res., 2009, 15(2)). Clinically, the pronounced expression of IDO1 found in several human tumor types has been correlated with negative prognosis and poor survival rate (Zou, Nature Rev. Cancer, 2005, 5:263-274; Zamanakou et al., Immunol. Lett. 2007, 111(2):69-75). Serum from cancer patients has higher kynurenine/tryptophan ratio, a higher number of circulating T-regs, and increased effector T cell apoptosis when compared to serum from healthy volunteers (Suzuki et al., Lung Cancer, 2010, 67:361-365). Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase has been studied by Pilotte et al. (Pilotte et al., Proc. Natl. Acad. Sci. USA, 2012, Vol. 109(7):2497-2502). Thus, decreasing the rate of kynurenine production by inhibiting IDO1 and/or TDO may be beneficial to cancer patients.
      IDO1 and IDO2 are implicated in inflammatory diseases. IDO1 knock-out mice don’t manifest spontaneous disorders of classical inflammation and existing known small molecule inhibitors of IDO do not elicit generalized inflammatory reactions (Prendergast et al. Curr Med Chem. 2011; 18(15):2257-62). Rather, IDO impairment alleviates disease severity in models of skin cancers promoted by chronic inflammation, inflammation-associated arthritis and allergic airway disease. Moreover, IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in autoimmune arthritis. IDO2 knock-out mice have reduced joint inflammation compared to wild-type mice due to decreased pathogenic autoantibodies and Ab-secreting cells (Merlo et al. J. Immunol. (2014) vol. 192(5) 2082-2090). Thus, inhibitors of IDO1 and IDO2 are useful in the treatment of arthritis and other inflammatory diseases.
      Kynurenine pathway dysregulation and IDO1 and TDO play an important role in the brain tumors and are implicated in inflammatory response in several neurodegenerative disorders including multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, stroke, amyotrophic lateral schlerosis, dementia (Kim et al., J. Clin. Invest, 2012, 122(8):2940-2954; Gold et al., J. Neuroinflammation, 2011, 8:17; Parkinson’s Disease, 2011, Volume 2011). Immunosuppression induced by IDO1 activity and the Kynurenine metabolites in the brain may be treated with inhibitors of IDO1 and/or TDO. For example, circulating T-reg levels were found to be decreased in patient with glioblastoma treated with anti-viral agent inhibitors of IDO1 (Soderlund, et al., J. Neuroinflammation, 2010, 7:44).
      Several studies have found Kynurenine pathway metabolites to be neuroactive and neurotoxic. Neurotoxic kynurenine metabolites are known to increase in the spinal cord of rats with experimental allergic encephalomyelitis (Chiarugi et al., Neuroscience, 2001, 102(3):687-95). The neurotoxic effects of Kynurenine metabolities is exacerbated by increased plasma glucose levels. Additionally, changes in the relative or absolute concentrations of the kynurenines have been found in several neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease, stroke and epilepsy (Németh et al., Central Nervous System Agents in Medicinal Chemistry, 2007, 7:45-56; Wu et al. 2013; PLoS One; 8(4)).
      Neuropsychiatric diseases and mood disorders such as depression and schizophrenia are also said to have IDO1 and Kynurenine dysregulation. Tryptophan depletion and deficiency of neurotransmitter 5-hydroxytryptamine (5-HT) leads to depression and anxiety. Increased IDO1 activity decreases the synthesis of 5-HT by reducing the amount of Tryptophan availability for 5-HT synthesis by increasing Tryp catabolism via the kynurenine pathway (Plangar et al. (2012) Neuropsychopharmacol Hung 2012; 14(4): 239-244). Increased IDO1 activity and levels of both kynurenine and kynurenic acid have been found in the brains of deceased schizophrenics (Linderholm et al., Schizophrenia Bulletin (2012) 38: 426-432)). Thus, inhibition of IDO1, IDO1, and TDO may also be an important treatment strategy for patients with neurological or neuropsychiatric disease or disorders such as depression and schizophrenia as well as insomnia.
      Kynurenine pathway dysregulation and IDO1 and/or TDO activity also correlate with cardiovascular risk factors, and kynurenines and IDO1 are markers for Atherosclerosis and other cardiovascular heart diseases such as coronary artery disease (Platten et al., Science, 2005, 310(5749):850-5, Wirlietner et al. Eur J Clin Invest. 2003 July; 33(7):550-4) in addition to kidney disease. The kynurenines are associated with oxidative stress, inflammation and the prevalence of cardiovascular disease in patients with end-stage renal disease (Pawlak et al., Atherosclerosis, 2009, (204)1:309-314). Studies show that kynurenine pathway metabolites are associated with endothelial dysfunction markers in the patients with chronic kidney disease (Pawlak et al., Advances in Medical Sciences, 2010, 55(2):196-203).

///////CRD1152, CRD-1152, CRD 1152, CURADEV PHARMA PRIVATE LTD, ROCHE, IDO1 and TDO inhibitors, COLLABORATION, CANCER, indoleamine-2,3-dioxygenase-1, Hoffmann-La Roche, kynurenine pathway regulators, solid tumors

Dr. Reddy’s Laboratories CEO G V Prasad has been recognized as one of India’s top 5 most valuable CEOs

April 5, 2016 10:26 am / 1 Comment on Dr. Reddy’s Laboratories CEO G V Prasad has been recognized as one of India’s top 5 most valuable CEOs


reddyDr. Reddy's Laboratories

Dr. Reddy’s Laboratories

CEO G V Prasad has been recognized as one of India’s top 5 most valuable CEOs Read more: bit.ly/CEOsRanking

http://businessworld.in/article/How-We-Ranked-The-CEOs/31-03-2016-92402/

 

////////Dr. Reddy’s Laboratories,  CEO , G V Prasad, India’s top 5 most valuable CEOs

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