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Capromorelin in phase 2……Ghrelin Receptor Agonist

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Capromorelin skeletal.svg

Capromorelin

N-[(2R)-1-[(3aR)-2-methyl-3-oxo-3a-(phenylmethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-1-oxo-3-(phenylmethoxy)propan-2-yl]-2-amino-2-methylpropanamide

2-Amino-N-[2-[3a(R)-benzyl-2-methyl-3-oxo-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-5-yl]-1(R)-(benzyloxymethyl)-2-oxoethyl]isobutyramide

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))

505.6086

C28 H35 N5 O4

CP-424391
RQ-00000005
CP-424391-18 (tartrate)

Pfizer (Originator)
RaQualia

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

 https://www.google.com/patents/WO1997024369A1?cl=en

…………………………..

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.

 

References

  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

Researchers

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

12-31-1998
TREATMENT OF INSULIN RESISTANCE WITH GROWTH HORMONE SECRETAGOGUES

 

3-16-2005
Treatment of insulin resistance
2-2-2005
Neuroprotective drug
1-7-2004
Process for preparing growth hormone secretagogues
4-2-2003
Process for preparing growth hormone secretagogues
9-11-2002
Treatment of insulin resistance with growth hormone secretagogues
9-27-2000
Heterocyclic compounds
8-30-2000
Growth hormone secretagogues
8-23-2000
Heterocyclic compounds
12-24-1999
THERAPEUTIC COMBINATIONS OF (SELECTIVE) ESTROGEN RECEPTOR MODULATORS (SERM) AND GROWTH HORMONE SECRETAGOGUES (GHS) FOR TREATING MUSCULOSKELETAL FRAILTY
4-23-1999
PROSTAGLANDIN AGONISTS AND THEIR USE TO TREAT BONE DISORDERS
10-19-2011
Method of Stimulating the Motility of the Gastrointestinal System Using Growth Hormone Secretagogues
12-5-2008
Methods of treating emesis using growth hormone secretagogues
10-24-2008
Growth-Hormone Secretagogues
8-29-2008
Method of treating cell proliferative disorders using growth hormone secretagogues
2-29-2008
Treatment For Alzheimer’s Disease And Related Conditions
8-17-2007
Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues
5-3-2007
GROWTH-HORMONE SECRETAGOGUES
8-18-2006
Combination of gh secret agogues and pde4 inhibitors for the treatment of alzheimers disease
11-25-2005
Method of reducing C-reactive protein using growth hormone secretagogues
3-25-2005
Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin D derivatives and a growth hormone secretagogue

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DR ANTHONY CRASTO

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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 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 amcrasto@gmail.com, 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......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

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