New Drug Approvals

Home » 2014 » May (Page 3)

Monthly Archives: May 2014


Blog Stats

  • 2,702,070 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,444 other followers

Follow New Drug Approvals on



Flag Counter


Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,444 other followers



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 GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 30 year tenure till date Dec 2017, 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 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →



Flag Counter

Lung cancer screening could cost Medicare billions

Atasteofcreole's Blog

Every person covered by Medicare would shell out an additional $3 a month if the government agreed to pay to screen certain current and former smokers for lung cancer, a new study estimates.

It would cost Medicare $2 billion a year to follow recent advice to offer these lung scans, the study found.

Joshua Roth of the Fred Hutchinson Cancer Research Center in Seattle said the researchers were merely tallying the cost and were not “judging value” or saying whether Medicare should pay it. He led the study, which was released Wednesday.

Lung cancer is the world’s top cancer killer, mainly because it’s usually found too late for treatment to do much good. Most deaths involve Medicare-age people, and most are due to smoking.

Recently, a major study found that annual CT scans could cut the chances of dying from lung cancer by up to…

View original post 35 more words


Astellas’ Dificlir (fidaxomicin) could save NHS thousands of pounds






C52H74Cl2O18   Molecular Weight: 1058.03916 

US FDA:link         Launched – 2011   Clostridium difficile-associated diarrhea


Astellas' Dificlir could save NHS thousands of pounds

Using Astellas’ Dificlir (fidaxomicin) as a first-line treatment for clostridium difficile infection (CDI) is not only clinically effective but could also save the National Health Service thousands of pounds compared to the standard of care, according to data from a late-stage study

Read more at:


Fidaxomicin (trade names DificidDificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrummacrocyclic antibiotic drugs.[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.[3][4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species ofbacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.[5] [6]

It is marketed by Cubist Pharmaceuticals after acquisition of its the originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection. Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient’s clinical status. It is currently one of the most expensive antibiotics approved for use. A 20 tab pack costs upwards of £1350.[7]

Fidaxomicin works by inhibiting the bacterial enzyme RNA polymerase, resulting in the death of Clostridium difficile.[8] It is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.[3]

Approvals and indications

For the treatment of CDAD (Clostridium difficile-Associated diarrhea), the drug won an FDA advisory panel’s unanimous approval on April 5, 2011.[14] and full FDA approval on May 27, 2011.[15]

Fidaxomicin is an antibiotic approved and launched in 2011 in the U.S. for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adults 18 years of age and older. In September 2011, the product received a positive opinion in the E.U. and final approval was assigned in December 2011. First E.U. launch took place in the U.K. in June 2012. Optimer Pharmaceuticals is conducting phase III clinical trials for the prevention of Clostridium difficile-associated diarrhea in patients undergoing hematopoietic stem cell transplant. Preclinical studies are ongoing for potential use in the prevention of methicillin-resistant Staphylococcus (MRS) infection. Early clinical studies had been under way for the prevention and treatment of vancomycin-resistant enterococcal (VRE) infection; however, no recent development has been reported for this indication.

The compound is a novel macrocyclic antibiotic that is produced by fermentation. Its narrow-spectrum activity is highly selective for C. difficile, thus preserving gut microbial ecology, an important consideration for the treatment of CDAD.

In May 2005, Par Pharmaceutical and Optimer entered into a joint development and collaboration agreement for fidaxomicin. However, rights to the compound were returned to Optimer in 2007. The compound was granted fast track status by the FDA in 2003. In 2010, orphan drug designation was assigned to fidaxomicin in the U.S. by Optimer Pharmaceuticals for the treatment of pediatric Clostridium difficile infection (CDI). In 2011, the compound was licensed by Optimer Pharmaceuticals to Astellas Pharma in Europe and certain countries in the Middle East, Africa, the Commonwealth of Independent States (CIS) and Japan for the treatment of CDAD. In 2011, fidaxomicin was licensed to Cubist by Optimer Pharmaceuticals for comarketing in the U.S. for the treatment of CDAD. In July 2012, the product was licensed by Optimer Pharmaceuticals to Specialised Therapeutics Australia in AU and NZ for the treatment of Clostridium difficile-associated infection. OBI Pharma holds exclusive commercial rights in Taiwan, where the compound was approved for the treatment of CDAD in September 2012, and in December 2012, the product was licensed to AstraZeneca in South America with commercialization rights also for the treatment of CDAD. 

Clinical trials

Good results were reported in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment ofClostridium difficile infection (CDI)[9][10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).[11] Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next 4 weeks.[12]

Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.


  1.  “DIFICID®” (PDF). TGA eBusiness Services. Specialised Therapeutics Australia Pty Ltd. 23 April 2013. Retrieved 31 March 2014.
  2.  Revill, P.; Serradell, N.; Bolós, J. (2006). “Tiacumicin B”. Drugs of the Future 31 (6): 494. doi:10.1358/dof.2006.031.06.1000709.
  3.  “Dificid, Full Prescribing Information”. Optimer Pharmaceuticals. 2013.
  4.  “Fidaxomicin”. Drugs in R&D 10: 37. 2012. doi:10.2165/11537730-000000000-00000.
  5.  Louie, T. J.; Emery, J.; Krulicki, W.; Byrne, B.; Mah, M. (2008). “OPT-80 Eliminates Clostridium difficile and is Sparing of Bacteroides Species during Treatment of C. Difficile Infection”Antimicrobial Agents and Chemotherapy 53 (1): 261–3. doi:10.1128/AAC.01443-07.PMC 2612159PMID 18955523.
  6.  Johnson, Stuart (2009). “Recurrent Clostridium difficile infection: A review of risk factors, treatments, and outcomes”. Journal of Infection58 (6): 403–10. doi:10.1016/j.jinf.2009.03.010PMID 19394704.
  8.  Srivastava, Aashish; Talaue, Meliza; Liu, Shuang; Degen, David; Ebright, Richard Y; Sineva, Elena; Chakraborty, Anirban; Druzhinin, Sergey Y; Chatterjee, Sujoy; Mukhopadhyay, Jayanta; Ebright, Yon W; Zozula, Alex; Shen, Juan; Sengupta, Sonali; Niedfeldt, Rui Rong; Xin, Cai; Kaneko, Takushi; Irschik, Herbert; Jansen, Rolf; Donadio, Stefano; Connell, Nancy; Ebright, Richard H (2011). “New target for inhibition of bacterial RNA polymerase: ‘switch region'”Current Opinion in Microbiology 14 (5): 532–43.doi:10.1016/j.mib.2011.07.030PMC 3196380PMID 21862392.
  9.  “Optimer’s North American phase 3 Fidaxomicin study results presented at the 49th ICAAC” (Press release). Optimer Pharmaceuticals. September 16, 2009. Retrieved May 7, 2013.
  10.  “Optimer Pharmaceuticals Presents Results From Fidaxomicin Phase 3 Study for the Treatment” (Press release). Optimer Pharmaceuticals. May 17, 2009. Retrieved May 7, 2013.
  11.  Golan Y, Mullane KM, Miller MA (September 12–15, 2009). “Low recurrence rate among patients with C. difficile infection treated with fidaxomicin”. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
  12.  Gorbach S, Weiss K, Sears P, et al (September 12–15, 2009). “Safety of fidaxomicin versus vancomycin in treatment of Clostridium difficile infection”. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
  13.  Louie, Thomas J.; Miller, Mark A.; Mullane, Kathleen M.; Weiss, Karl; Lentnek, Arnold; Golan, Yoav; Gorbach, Sherwood; Sears, Pamela; Shue, Youe-Kong; Opt-80-003 Clinical Study, Group (2011). “Fidaxomicin versus Vancomycin forClostridium difficileInfection”. New England Journal of Medicine 364 (5): 422–31. doi:10.1056/NEJMoa0910812PMID 21288078.
  14.  Peterson, Molly (Apr 5, 2011). “Optimer Wins FDA Panel’s Backing for Antibiotic Fidaxomicin”. Bloomberg.
  15.  Nordqvist, Christian (27 May 2011). “Dificid (fidaxomicin) Approved For Clostridium Difficile-Associated Diarrhea”Medical News Today.

India business robust in terms of growth: Glenmark….videos




India business robust in terms of growth: Glenmark on Q1…/news/video-india-business-robust…

Aug 2, 2013

NDTV Profit News Video Clip on India business robust in terms of growth: … chairman and managing director …

Capromorelin in phase 2……Ghrelin Receptor Agonist

Capromorelin skeletal.svg




CP-424391-18, (3ar)-3a-benzyl-2-methyl-5-(2-methylalanyl-o-benzyl-d-seryl)-3-oxo-3,3a,4,5,6,7-hexahydro-2h-pyrazolo[4,3-c]pyridine

Gastro-esophageal reflux disease (GERD)

193273-66-4 free form
193270-49-4 (monoHCl)
193273-67-5 (monomesylate)
193273-69-7 (L-tartrate(1:1))


C28 H35 N5 O4

CP-424391-18 (tartrate)

Pfizer (Originator)

Phase II

Capromorelin (CP-424,391) is an investigational medication developed by the Pfizer drug company.[2] [3] It functions as a growth hormone secretagogue and ghrelin mimetic which causes the body to secrete human growth hormone in a way usually seen at puberty and in young adulthood. Initial studies have shown the drug to directly raise insulin growth factor 1 (IGF-1) and growth hormone levels.[4]

The drug is being considered for its therapeutic value in aging adults because elderly people have much lower levels of growth hormone and less lean muscle mass, which can result in weakness and frailty.[5]

In a one-year treatment trial (starting 1999) with 395 seniors between 65 and 84 years old, patients who received the drug gained an average of 3 lb (1.4 kg) in lean body mass in the first six months and also were better able to walk in a straight line in a test of balance, strength and coordination. After 12 months, patients receiving capromorelin also had an improved ability to climb stairs, however the results were not good enough to continue the trial for the 2nd planned year.[6]

Capromorelin, however, has not been approved by major regulatory bodies such as the World Health Organization, the European Medicines Agency or the United States FDA. In the U.S. at least, approval is not expected to be forthcoming any time soon, because the FDA does not consider aging a disease, and so requires extraordinary evidence of benefit and non-toxicity to approve a drug for use as an anti-aging agent.[7]

Ghrelin is a peptide that promotes a growth hormone secreted by the stomach and exhibits a variety of physiological effects, including the promotion of appetite, gastrointestinal tract motility and stomach acid secretion, as well as improved heart function. Capromorelin (RQ-00000005) is a ghrelin receptor agonist and, because it has been shown to increase body weight without increasing body fat and to improve motility and appetite in the elderly, it has the potential for many uses, including frailty and GERD.


WO 1997024369


EP 0869968; JP 1999501945; WO 9724369

The intermediate dipeptide (VI) was prepared by two similar ways. Treatment of N-Boc-O-benzyl-D-serine (I) with MeI and K2CO3 produced the methyl ester (II). Subsequent deprotection of the Boc group of (II) with trifluoroacetic acid gave aminoester (III), which was coupled with N-Boc-alpha-methylalanine (IV) using EDC and HOBt yielding (V). Hydrolysis of the resulting dipeptide ester (V) then provided intermediate (VI). In an alternative procedure, N-Boc-alpha-methyl alanine (IV) was activated as the N-hydroxysuccinimidyl ester (VII), which was condensed with O-benzyl-D-serine (VIII) to produce dipeptide (VI).

Methyl 4-oxopiperidine-3-carboxylate (IX) was protected as the tert-butyl carbamate (X) with Boc2O. This was alkylated with benzyl bromide in the presence of NaH to provide the racemic benzyl derivative (XI). Subsequent cyclization of (XI) with methylhydrazine produced the pyrazolopyridine (XII), which was deprotected with trifluoroacetic acid. The resulting amine (XIII) was then coupled with dipeptide (VI) using EDC and HOBt to afford the diastereomeric amides (XIV). After chromatographic isolation of the (R,R)-diastereoisomer, acid deprotection of the Boc group furnished the title compound.



  1. Khojasteh-Bakht SC, O’donnell JP, Fouda HG, Potchoiba MJ. Metabolism, pharmacokinetics, tissue distribution, and excretion of [14C]CP-424391 in rats. Drug Metabolism and Disposition. 2005 Jan;33(1):190-9. PMID 15486077
  2. Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Murray MC, Cook ER, DiBrino JN, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Lewis SK, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, Pettersen JC, DaSilva-Jardine PA, Wilson TC, Thompson DD. Discovery and biological characterization of capromorelin analogues with extended half-lives. Bioorganic and Medicinal Chemistry Letters. 2002 Nov 18;12(22):3279-82. PMID 12392732
  3. Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Cook ER, DiBrino JN, Campeta AM, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, DaSilva-Jardine PA, Wilson TC, Thompson DD. Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin. Bioorganic and Medicinal Chemistry. 2003 Feb 20;11(4):581-90. PMID 12538023
  4. Pan LC, Carpino PA, Lefker BA, Ragan JA, Toler SM, Pettersen JC, Nettleton DO, Ng O, Pirie CM, Chidsey-Frink K, Lu B, Nickerson DF, Tess DA, Mullins MA, MacLean DB, DaSilva-Jardine PA, Thompson DD. Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine growth hormone secretagogue. Endocrine. 2001 Feb;14(1):121-32. PMID 11322494
  5. Thompson DD. Aging and sarcopenia. Journal of Musculoskeletal and Neuronal Interactions. 2007 Oct-Dec;7(4):344-5. PMID 18094505
  6. Heidi K. White, Charles D. Petrie, William Landschulz, David MacLean, Ann Taylor, Kenneth Lyles, Jeanne Y. Wei, Andrew R. Hoffman, Roberto Salvatori, Mark P. Ettinger, Miriam C. Morey, Marc R. Blackman, George R. Merriam for the Capromorelin Study Group. Effects of an Oral Growth Hormone Secretagogue in Older Adults. Journal of Clinical Endocrinology & Metabolism. April 2009, Vol. 94, No. 4 1198-1206. doi:10.1210/jc.2008-0632. PMID 19174493
  7. Hersch EC, Merriam GR. Growth hormone (GH)-releasing hormone and GH secretagogues in normal aging: Fountain of Youth or Pool of Tantalus? Clinical Interventions in Aging. 2008;3(1):121-9. PMID 18488883


Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.
Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues
216th ACS Natl Meet (August 23-27, Boston) 1998, Abst MEDI 276



Treatment of insulin resistance
Neuroprotective drug
Process for preparing growth hormone secretagogues
Process for preparing growth hormone secretagogues
Treatment of insulin resistance with growth hormone secretagogues
Heterocyclic compounds
Growth hormone secretagogues
Heterocyclic compounds
Method of Stimulating the Motility of the Gastrointestinal System Using Growth Hormone Secretagogues
Methods of treating emesis using growth hormone secretagogues
Growth-Hormone Secretagogues
Method of treating cell proliferative disorders using growth hormone secretagogues
Treatment For Alzheimer’s Disease And Related Conditions
Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues
Combination of gh secret agogues and pde4 inhibitors for the treatment of alzheimers disease
Method of reducing C-reactive protein using growth hormone secretagogues
Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a growth hormone secretagogue



Anthony Melvin Crasto Ph.D





Taltirelin Талтирелин for Treatment of Neurodegenerative Diseases,



Taltirelin Талтирелин



launched 2000 by Mitsubishi Tanabe Pharma


 Tanabe Seiyaku Co., Ltd.


Taltirelin tetrahydrate, Taltirelin hydrate, 201677-75-0, TA 0910
Molecular Formula: C17H31N7O9   Molecular Weight: 477.46954

Taltirelin (marketed under the tradename Ceredist) is a thyrotropin-releasing hormone (TRH) analog, which mimics the physiological actions of TRH, but with a much longer half-life and duration of effects,[1] and little development of tolerance following prolonged dosing.[2] It has nootropic,[3] neuroprotective[4] and analgesic effects.[5]

Taltirelin is primarily being researched for the treatment of spinocerebellar ataxia; limited research has also been carried out with regard to other neurodegenerative disorders, e.g., spinal muscular atrophy.[6][7][8]

Taltirelin is a thyrotropin-releasing hormone (TRH) analog that was first commercialized by Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) in Japan in 2000 for the oral treatment of ataxia due to spinocerebellar degeneration.

In 2008, the company filed a regulatory application seeking approval of taltirelin orally disintegrating tablets for the treatment of spinocerebellar degeneration, and in 2009 the approval was received for this formulation.

TRH is a tripeptide hormone that stimulates the release of thyroid-stimulating hormone and prolactin by the anterior pituitary. TRH is produced by the hypothalamus and travels across the median eminence to the pituitary via the hypophyseal portal system.

Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a superagonist at TRH-R


Synthesis and central nervous system actions of thyrotropin-releasing hormone analogues containing a dihydroorotic acid moiety
J Med Chem 1990, 33(8): 2130\



(1) 1.56 g of 1-methyl-L-4,5-dihydroorotic acid and 1.15 g of N-hydroxysuccinimide are dissolved in 30 ml of dimethylformamide, and 2.06 g of dicyclohexylcarbodiimide are added thereto at 0° C. The mixture is stirred at room temperature for 2 hours. The solution thus obtained is hereinafter referred to as “Solution A”. On the other hand, 3.43 g of benzyl L-histidyl-L-prolinate.2HCl are dissolved in dimethylformamide, and 1.67 g of triethylamine are added thereto. The mixture is stirred at 0° C. for 20 minutes, and insoluble materials are filtered off. The filtrate is added to “Solution A”, and the mixture is stirred at 0° C. for 4 hours and then at 10° C. for one day. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure at 40° C. to remove dimethylformamide. The residue is dissolved in water, and insoluble materials are filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. The column is washed with 500 ml of water, 500 ml of 20% methanol and 300 ml of 50% methanol, successively. Then, the desired product is eluted with 70% methanol. The fractions which are positive to the Pauly’s reaction are collected from the eluate and concentrated under reduced pressure, whereby 3.65 g of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are obtained as an oil.

IRνmax chloroform (cm-1) 3300, 1725, 1680.

650 mg of the product obtained above are dissolved in 1 N-HCl and then lyophilized to give 690 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate.HCl.H2 O as powder.

[α]D 22 : -39.8° (C=0.5, H2 O).

IRνmax nujol (cm-1): 1720, 1640-1680.

NMR (DMSO-d6, δ): 1.7-2.4 (m, 4H), 2.90 (s, 3H), 2.4-3.9 (m, 6H), 3.9-4.2 (m, 1H), 4.3-4.5 (m, 1H), 4.6-5.0 (m, 1H), 5.09 (s, 2H), 7.2-7.5 (m, 5H), 8.96 (s, 1H).

Mass (m/e): 496 (M+).

(2) 700 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are dissolved in 20 ml of methanol, and 20 mg of palladium-black are added thereto. The mixture is stirred at room temperature for 3 hours in hydrogen gas. 20 ml of water are added to the reaction mixture, and the catalyst is filtered off. The filtrate is evaporated to remove solvent. The residue is crystallized with methanol, whereby 290 mg of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline.5/4 H2 O are obtained.

M.p.: 233°-236° C. (decomp.).

[α]D 20 : -17.2° (C=0.5, H2 O).

IRνmax nujol (cm-1): 1715, 1680, 1630.

NMR (D2 O, δ): 1.7-2.4 (m, 4H), 2.6-3.9 (m, 6H), 3.03 (s, 3H), 4.0-4.45 (m, 2H), 4.95 (t, 1H), 7.27 (s, 1H), 8.57 (s, 1H).

(3) A mixture of 4.29 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline, 1.15 g of N-hydroxysuccinimide, 2.26 g of dicyclohexylcarbodiimide and 30 ml of dimethylformamide is stirred at 0° C. for 40 minutes and at room temperature for 80 minutes. 30 ml of 15% ammonia-methanol are then added to the mixture at 0° C., and the mixture is stirred at 0° C. for 30 minutes and at room temperature for one hour. Insoluble materials are filtered off, and the filtrate is evaporated to remove dimethylformamide. The residue is dissolved in 20 ml of water, and insoluble materials are again filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. After the column is washed with 2 liters of water, the desired product is eluted with 10% methanol. The fractions which are positive to the Pauly’s reaction are collected and concentrated under reduced pressure. The residue is dissolved in 10 ml of water, and allowed to stand in a refrigerator. Crystalline precipitates are collected by filtration, washed with water, and then dried at 25° C. for one day, whereby 3.3 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinamide.7/2 H2 O are obtained.

M.p.: 72°-75° C.

[α]D 25 : -13.6° (C=1, H2 O).

IRνmax nujol (cm-1): 3400, 3250, 1710, 1660, 1610, 1540.


  1. Fukuchi, I.; Asahi, T.; Kawashima, K.; Kawashima, Y.; Yamamura, M.; Matsuoka, Y.; Kinoshita, K. (1998). “Effects of taltirelin hydrate (TA-0910), a novel thyrotropin-releasing hormone analog, on in vivo dopamine release and turnover in rat brain”. Arzneimittel-Forschung 48 (4): 353–359. PMID 9608876.
  2. Asai, H.; Asahi, T.; Yamamura, M.; Yamauchi-Kohno, R.; Saito, A. (2005). “Lack of behavioral tolerance by repeated treatment with taltirelin hydrate, a thyrotropin-releasing hormone analog, in rats”. Pharmacology Biochemistry and Behavior 82 (4): 646–651. doi:10.1016/j.pbb.2005.11.004. PMID 16368129.
  3. Yamamura, M.; Suzuki, M.; Matsumoto, K. (1997). “Synthesis and pharmacological action of TRH analog peptide (Taltirelin)”. Nihon yakurigaku zasshi. Folia pharmacologica Japonica. 110 Suppl 1: 33P–38P. PMID 9503402.
  4. Urayama, A.; Yamada, S.; Kimura, R.; Zhang, J.; Watanabe, Y. (2002). “Neuroprotective effect and brain receptor binding of taltirelin, a novel thyrotropin-releasing hormone (TRH) analogue, in transient forebrain ischemia of C57BL/6J mice”. Life Sciences 72 (4–5): 601–607. doi:10.1016/S0024-3205(02)02268-3. PMID 12467901.
  5. Tanabe, M.; Tokuda, Y.; Takasu, K.; Ono, K.; Honda, M.; Ono, H. (2009). “The synthetic TRH analogue taltirelin exerts modality-specific antinociceptive effects via distinct descending monoaminergic systems”. British Journal of Pharmacology 150 (4): 403–414. doi:10.1038/sj.bjp.0707125. PMC 2189720. PMID 17220907.
  6. Takeuchi, Y.; Miyanomae, Y.; Komatsu, H.; Oomizono, Y.; Nishimura, A.; Okano, S.; Nishiki, T.; Sawada, T. (1994). “Efficacy of Thyrotropin-Releasing Hormone in the Treatment of Spinal Muscular Atrophy”. Journal of Child Neurology 9 (3): 287–289. doi:10.1177/088307389400900313. PMID 7930408.
  7. Tzeng, A. C.; Cheng, J.; Fryczynski, H.; Niranjan, V.; Stitik, T.; Sial, A.; Takeuchi, Y.; Foye, P.; Deprince, M.; Bach, J. R. (2000). “A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: A preliminary report”. American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 79 (5): 435–440. doi:10.1097/00002060-200009000-00005. PMID 10994885.
  8. Kato, Z.; Okuda, M.; Okumura, Y.; Arai, T.; Teramoto, T.; Nishimura, M.; Kaneko, H.; Kondo, N. (2009). “Oral Administration of the Thyrotropin-Releasing Hormone (TRH) Analogue, Taltireline Hydrate, in Spinal Muscular Atrophy”. Journal of Child Neurology 24 (8): 1010–1012. doi:10.1177/0883073809333535. PMID 19666885.
    • EP 168 042 (Tanabe Seiyaku; appl. 10.7.1985; GB-prior. 10.7.1984).
    • JP 62 234 029 (Tanabe Seiyaku; J-prior. 27.12.1985).
    • Suzuki, M. et al.: J. Med. Chem. (JMCMAR) 33 (8), 2130-2137 (1990).

External links

Lilly’s diabetes drug peglispro outshines world’s most popular insulin

 Lilly's diabetes drug outshines world's most popular insulin
insulin peglispro
SYNONYMS macrogol 20000 pegylated insulin lispro: [28B-(6-N-{[ω-methoxypoly(oxyethylene)]carbonyl}-L-lysine), 29B-L-proline]human insulin
CAS 1200440-65-8
insulin peglispro


Lilly’s diabetes drug outshines world’s most popular insulin

World News | May 13, 2014

Late-stage clinical data has shown Lilly’s experimental diabetes drug Peglispro to be better at reducing blood sugar in patients with type II diabetes than Sanofi’s Lantus – the world’s most prescribed insulin.

The US drugmaker says it expects to file for approval of its basal insulin (BIL) by the first quarter of next year, after three Phase III studies showed it induced “a statistically superior reduction in HbA1c” compared with Lantus.



New breast cancer stem cell findings explain how cancer spreads


Breast cancer stem cells exist in two different states and each state plays a role in how cancer spreads, according to an international collaboration of researchers. Their finding sheds new light on the process that makes cancer a deadly disease.

View original post

GSK2606414 is an orally available, potent, and selective PERK inhibitor

GSK2606414 structure




CAS: 1337531-36-8

 Formula: C24H20F3N5O
Exact Mass: 451.16199

Glaxosmithkline Llc  innovator

CS-1428, QC-9698, GSK 2606414, KB-145925, GSK2606414|1337531-36-8|GSK-2606414

  nmr       ………

GSK2606414  is an orally available, potent, and selective PERK inhibitor. GSK2606414 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. (12/13/2013).

GSK2606414 structure.png

In vitro protocol:

J Med Chem. 2012 Aug 23;55(16):7193-207

In vivo protocol:

J Med Chem. 2012 Aug 23;55(16):7193-207


The chemical structures of GSK2606414  and GSK2656157 are very similar. The following graphic is a side-by-side comparison.

GSK2606414-GSK2656157 structure


GSK2606414 is a drug which is the first selective inhibitor discovered for the enzyme protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which is involved in various processes relating to cancer and neurodegenerative disorders. GSK2606414 was found to be a potent and selective inhibitor of PERK, with good oral bioavailability and blood-brain barrier penetration.[1] PERK mediates the unfolded protein response pathway which is involved in the initiation of protein synthesis, and this pathway has been implicated in the neurotoxicity of various diseases including prion and Alzheimer’s diseases. Treatment with GSK2606414 was found to be neuroprotective in mice against damage caused by prions, and prevented the development of cognitive deficits and other clinical manifestations of prion disease. Extension of lifespan in treated mice was, however, not recorded. However, side effects such as weight loss and elevated blood glucose levels were also observed, likely due to unwanted inhibition of PERK in the pancreas gland, where it is involved in regulating insulin production.[2]

WO 2011119663

Example 35

5-{1 -[(3-fluorophenyl)acetyl]-2,3-dihydro-1 H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-amine

Figure imgf000116_0001

In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1 H-indol-5-yl)-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine2HCI (70.6 mg, 0.209 mmol), (3-fluorophenyl)acetic acid (32.2 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig’s base (0.146 mL, 0.836 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The solid was filtered and dried to afford a white solid as the product. 1H NMR (400 MHz, DMSO- cfe) δ ppm 3.23 (t, J=8.46 Hz, 2 H), 3.73 (s, 3 H), 3.92 (s, 2 H), 4.19 – 4.26 (m, 2 H), 7.08 – 7.1 1 (m, 1 H), 7.12 – 7.17 (m, 2 H), 7.23 (d, J=8.34 Hz, 1 H), 7.25 (s, 1 H), 7.31 (s, 1 H), 7.36 (s, 1 H), 7.39 (d, J=6.82 Hz, 1 H), 8.10 – 8.17 (m, 2 H).


  1. Axten, J. M.; Medina, J. S. R.; Feng, Y.; Shu, A.; Romeril, S. P.; Grant, S. W.; Li, W. H. H.; Heerding, D. A.; Minthorn, E.; Mencken, T.; Atkins, C.; Liu, Q.; Rabindran, S.; Kumar, R.; Hong, X.; Goetz, A.; Stanley, T.; Taylor, J. D.; Sigethy, S. D.; Tomberlin, G. H.; Hassell, A. M.; Kahler, K. M.; Shewchuk, L. M.; Gampe, R. T. (2012). “Discovery of 7-Methyl-5-(1-{\3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo\2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK)”. Journal of Medicinal Chemistry 55 (16): 7193–7207. doi:10.1021/jm300713s.PMID 22827572. edit
  2.  Moreno, J. A.; Halliday, M.; Molloy, C.; Radford, H.; Verity, N.; Axten, J. M.; Ortori, C. A.; Willis, A. E.; Fischer, P. M.; Barrett, D. A.; Mallucci, G. R. (2013). “Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice”. Science Translational Medicine 5 (206): 206ra138. doi:10.1126/scitranslmed.3006767. edit

1: Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA,  Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A, Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Hassell AM, Kahler KM, Shewchuk LM, Gampe RT. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012 Aug 23;55(16):7193-207. doi: 10.1021/jm300713s. Epub 2012 Aug 8. PubMed PMID: 22827572


%d bloggers like this: