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Zopolrestat

August 18, 2014 11:35 am / Leave a comment

Chemical structure for zopolrestat

Zopolrestat

CAS : 110703-94-1

110765-49-6 (Na salt)

3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid

2- [4-Oxo-3- [5- (trifluoromethyl) benzothiazol-2-ylmethyl] -3,4-dihydrophthalazin-1-yl] acetic acid

3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate

Pfizer Inc. INNOVATOR

2-[4-oxo-3-[5-(trifluoromethyl)benzothiazol-2-ylmethyl]-3,4-dihydrophthalazin-1-yl]acetic acid

Manufacturers’ Codes: CP-73850

MF: C19H12F3N3O3S

MW: 419.38

C 54.41%, H 2.88%, F 13.59%, N 10.02%, O 11.45%, S 7.65%

Crystals, mp 197-198°. pKa (dioxane/water): 5.46 (1:1); 6.38 (2:1). Log P (n-octanol/water): 3.43.

mp 197-198°

pKa: pKa (dioxane/water): 5.46 (1:1); 6.38 (2:1)

Log P: Log P (n-octanol/water): 3.43

Therap-Cat: Treatment of diabetic complications.

Keywords: Aldose Reductase Inhibitor.

synthesis

http://www.google.com/patents/US20140228319

2-(8-oxo-7-((5-trifluromethyl)-1H-benzo[d]imidazol-2-yl)methyl)7,8-dihydropyrazin[2,3-d]pyridazin-5-yl)acetic acid and [4-oxo-(5-trifluoromethyl-benzothaiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid (also known as zopolrestat), pharmaceutical compositions thereof and methods of treating diabetic complications in mammals comprising administering to mammals these salt and compositions. 2-(8-oxo-7-((5-trifluromethyl)-1H-benzo[d]imidazol-2-yl)methyl)8-dihydropyrazin[2,3-d]pyridazin-5-yl) acetic acid (formula II), is disclosed in WO 2012/009553 A1. Zopolrestat (formula III) is disclosed in U.S. Pat. No. 4,939,140.

Each of the patents, applications, and other references referred to herein are incorporated by reference. The diabetic complications include neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including myocardial infarction and cardiomyopathy. This invention is also directed to combinations of these salts and antihypertensive agents. These combinations are also useful in treating diabetic complications in mammals.

2-(8-oxo-7-((5-trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)8-dihydropyrazin[2,3-d]pyridazin-5-yl)acetic acid is prepared as disclosed in WO 2012/009553 A1, which is incorporated herein by reference. Zopolrestat is prepared as disclosed in U.S. Pat. No. 4,939,140.

Zopolrestat can be obtained by several different ways: 1) The reaction of 2- (4-oxo-3,4-dihydrophthalazin-1-yl) acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2- [3- (cyanomethyl) -4-oxo-3,4-dihydrophthalazin-1-yl] acetic acid ethyl ester (II), which is cyclized with 2-amino-4- (trifluoromethyl) thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV). Finally, this compound is hydrolyzed with KOH in methanol / water / THF. 2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride . (V) in hot DMF saturated with H2S 3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2- [3- (hydroxymethyl) -4-oxo-3,4 -dihydrophthalazin-1-yl] acetic acid ethyl ester (VI), which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII). Finally, this compound is treated with potassium cyanide and KI in acetone / water.

http://dmd.aspetjournals.org/content/26/11/1149/F2.expansion.html

……………………….

http://www.google.com/patents/EP0222576A2?cl=en

5=CF3 IS SUBS

EXAMPLE 7

[0051]

In accordance with Example 6, the following compounds are prepared:

……………………..

http://www.google.com/patents/US4939140

EXAMPLE 18 Sodium 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetateSodium methoxide (54 mg) was added to 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (0.4 g) in methanol 10 ml) at room temperature. After the addition was complete, a clear solution was obtained which was stirred for 15 minutes at room temperature. The excess methanol was evaporated. The residue was triturated with ether (20 ml) and filtered to obtain the product (0.43 g; m.p. 300° C.).EXAMPLE 19 3-(5-Trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate, dicyclohexylamine saltTo a mixture of 3-(5-trifluromethylbenzothiazol-2ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (0.42 g) in methanol (10 ml) was added dicyclohexylamine (0.2 g) in methanol (5 ml). The resulting clear solution was stirred at room temperature for 15 minutes and then evaporated to dryness. Trituration of the residue with ether (30 ml) gave a white solid (0.38 g; m.p. 207° C.).EXAMPLE 20 3-(5-Trifluoromethylbenzothiazol-2ylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid, meglumine saltA solution of 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (419 mg) and meglumine (196 mg) in methanol (50 ml) was stirred at room temperature for an hour and then evaporated to dryness. The residue was triturated with ether (25 ml), filtered and the collected solid was air dried (610 mg; m.p. 157° C.)……………………………

J. Med. Chem., 1991, 34 (1), pp 108–122

DOI: 10.1021/jm00105a018

http://pubs.acs.org/doi/abs/10.1021/jm00105a018

……………………………………

Mylari, Banavara L.; Zembrowski, William J.; Beyer, Thomas A.; Aldinger, Charles E.; Siegel, Todd W.
Journal of Medicinal Chemistry, 1992 , vol. 35, 12 p. 2155 – 2162

………………………………..

Mylari; Beyer; Scott; Aldinger; Dee; Siegel; Zembrowski
Journal of Medicinal Chemistry, 1992 , vol. 35, 3 p. 457 – 465

…………………………….

Literature References:

Aldose reductase inhibitor. Prepn: B. L. Mylari et al., EP 222576; E. R. Larson, B. L. Mylari, US 4939140(1987, 1990 both to Pfizer);

B. L. Mylari et al. J. Med. Chem. 34, 108 (1991).

Pharmacology: B. Tesfamariam et al., J. Cardiovasc.Pharmacol. 21, 205 (1993); B. Tesfamariam et al., Am. J. Physiol. 265, H1189 (1993).

Clinical pharmacokinetics: P. B. Inskeep et al., J. Clin. Pharmacol. 34, 760 (1994).

Zopolrestat < Rec INN; BAN; USAN >
Drugs Fut 1995, 20(1): 33

Synthesis of aldose reductase inhibitor, 3, 4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid
J Label Compd Radiopharm 1991, 29(2): 143

EP0222576	3-19-1992	HETEROCYCLIC OXOPHTHALAZINYL ACETIC ACIDS
WO9203432	3-6-1992	3-(5-TRIFLUOROMETHYLBENZOTHIAZOL-2-YLMETHYL)-4-OXO-3H-PHYTHALAZIN-1-YLACETIC ACID MONOHYDRATE
US4939140	7-4-1990	Heterocyclic oxophthalazinyl acetic acids

US2006062822	3-24-2006	Medical devices to treat or inhibit restenosis
EP1056729	12-30-2004	N-[(SUBSTITUTED FIVE-MEMBERED DI- OR TRIAZA DIUNSATURATED RING)CARBONYL]GUANIDINE DERIVATIVES FOR THE TREATMENT OF ISCHEMIA
EP1032424	10-7-2004	COMBINATION OF AN ALDOSE REDUCTASE INHIBITOR AND A GLYCOGEN PHOSPHORYLASE INHIBITOR COMBINATION OF AN ALDOSE REDUCTASE INHIBITOR AND A GLYCOGEN PHOSPHORYLASE INHIBITOR
EP0880964	9-30-2004	Aldose reductase inhibition in preventing or reversing diabetic cardiomyopathy
EP1022272	5-27-2004	SUBSTITUTED FUSED HETEROCYCLIC COMPOUNDS
EP1041068	4-15-2004	Compounds for treating and preventing diabetic complications
EP0873411	3-32-2004	IMPROVED MUTANTS OF (2,5-DKG) REDUCTASE A
EP0861666	12-18-2003	Pharmaceutical composition for use in treatment of diabetes
US2003212072	11-14-2003	Salts of zopolrestat
EP0792643	4-18-2002	Use of an aldose reductase inhibitor for reducing non-cardiac tissue damage

Кальцитонин, Calcitonin

August 18, 2014 10:27 am / Leave a comment

Molecular formula of calcitonin is C145H241N43O49S2
• Molecular weight is 3434.8 g/mol

Calcitonin-related polypeptide alpha
NMR solution structure of salmon calcitonin in SDS micelles.^[1]

Calcitonin

CAS Registry Number: 9007-12-9

Additional Names: Thyrocalcitonin; TCA; TCT

Therap-Cat: Calcium regulator.

The structural formula

Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide hormone that is produced in humansprimarily by the parafollicular cells (also known as C-cells) of the thyroid, and in many other animals in the ultimobranchial body.^[2] It acts to reduce blood calcium (Ca²⁺), opposing the effects of parathyroid hormone (PTH).^[3]

Calcitonin has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.^[4] It belongs to the calcitonin-like protein family.

UV – range

Solvent designation schedule	Methanol	Water	0.1М HCl	0.1M NaOH

Conditions : Concentration – 53 mg / 100 ml
The absorption maximum	278 nm	–	275 nm	–
	4.9	–	4.4	–
with	1670	–	1500	–

IR – spectrum

Wavelength (μm)

Wavenumber (cm ^-1 )

Links

UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
NIST/EPA/NIH Mass Spectral Library 2008
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Calcitonin-related polypeptide alpha

NMR solution structure of salmon calcitonin in SDS micelles.^[1]

Available structures

PDB

Ortholog search: PDBe, RCSB

[show]List of PDB id codes

Identifiers

Symbols

CALCA ; CALC1; CGRP; CGRP-I; CGRP1; CT; KC

External IDs

OMIM: 114130 MGI: 2151253 HomoloGene: 88401 ChEMBL: 5293 GeneCards: CALCA Gene

[show]Gene ontology

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 11:
14.99 – 14.99 Mb

Chr 7:
114.63 – 114.64 Mb

PubMedsearch

[1]

[2]

Biosynthesis and regulation

Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (CALCA). The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.

Secretion of calcitonin is stimulated by:

an increase in serum [Ca²⁺]^[5]
gastrin and pentagastrin.^[6]

Effects

The hormone participates in calcium (Ca²⁺) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH).

More specifically, calcitonin lowers blood Ca²⁺ levels in three ways:

Inhibits Ca²⁺ absorption by the intestines^[7]
Inhibits osteoclast activity in bones^[8]
Stimulates osteoblastic activity in bones. ^[8]
Inhibits renal tubular cell reabsorption of Ca²⁺ allowing it to be excreted in the urine^[9]^[10]

However, effects of calcitonin that mirror those of PTH include the following:

Inhibits phosphate reabsorption by the kidney tubules^[11]

In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation.

Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca²⁺. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.

Receptor

The calcitonin receptor, found on osteoclasts,^[12] and in kidney and regions of the brain, is a G protein-coupled receptor, which is coupled by G_s to adenylate cyclase and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.

Discovery

Calcitonin was purified in 1962 by Copp and Cheney.^[13] While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cellsof the thyroid gland.^[14]

Pharmacology

Salmon calcitonin is used for the treatment of:

It has been investigated as a possible non-operative treatment for spinal stenosis.^[16]

The following information is from the UK Electronic Medicines Compendium^[17]

General characteristics of the active substance

Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.

Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).

Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.

Characteristics in patients

There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.

Preclinical safety data

Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.

An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.

In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.

Pharmaceutical manufacture

Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by recombinant DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.^[17]

Uses of calcitonin

Treatments

Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.

Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.

This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”^[18]

Subcutaneous injections of calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder.^[19] However no further work on this potential application of calcitonin has been reported.

Diagnostics

It may be used diagnostically as a tumor marker for medullary thyroid cancer, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g., lymph nodes that are swollen) to establish whether they are metastasis of the original cancer.

Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:^[20]

females: 5 ng/L or pg/mL
males: 12 ng/L or pg/mL
children under 6 months of age: 40 ng/L or pg/mL
children between 6 months and 3 years of age: 15 ng/L or pg/mL

When over 3 years of age, adult cutoffs may be used

Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, Nonthyroidal oat cell carcinoma, Nonthyroidal small cell carcinoma and other nonthyroidal malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia and other gastrointestinal disorders, and pulmonary disease.^[21]

Structure

Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix.^[1] Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type.^[22]

The following are the amino acid sequences of salmon and human calcitonin:^[23]

salmon:

      Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro

human:

      Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro

Compared to salmon calcitonin, human calcitonin differs at 16 residues.

Description: Cellular and molecular coordination of tissues which secrete chemical compounds to regulate growth, reproduction, metabolism, and ion homeostasis.

References

^ Jump up to:^a ^b PDB 2glhAndreotti G, Méndez BL, Amodeo P, Morelli MA, Nakamuta H, Motta A (August 2006). “Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic alpha-helix”. J. Biol. Chem. 281 (34): 24193–203.doi:10.1074/jbc.M603528200. PMID 16766525.
Jump up^ Costoff A. “Sect. 5, Ch. 6: Anatomy, Structure, and Synthesis of Calcitonin (CT)”.Endocrinology: hormonal control of calcium and phosphate. Medical College of Georgia. Retrieved 2008-08-07.
Boron WF, Boulpaep EL (2004). “Endocrine system chapter”. Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. ISBN 1-4160-2328-3.
Jump up^ Costoff A. “Sect. 5, Ch. 6: Biological Actions of CT”. Medical College of Georgia. Retrieved 2008-08-07.
Costanzo, Linda S. (2007). BRS Physiology. Lippincott, Williams, & Wilkins. p. 263.ISBN 978-0-7817-7311-9.
Jump up^ Erdogan MF, Gursoy A, Kulaksizoglu M (October 2006). “Long-term effects of elevated gastrin levels on calcitonin secretion”. J Endocrinol Invest. 29 (9): 771–775.PMID 17114906.
Costoff A. “Sect. 5, Ch. 6: Effects of CT on the Small Intestine”. Medical College of Georgia. Retrieved 2008-08-07.
Costoff A. “Sect. 5, Ch. 6: Effects of CT on Bone”. Medical College of Georgia. Retrieved 2008-08-07.
Jump up^ Potts, John; Jüppner, Harald (2008). “Chapter 353. Disorders of the Parathyroid Gland and Calcium Homeostasis”. In Dan L. Longo, Dennis L. Kasper, J. Larry Jameson, Anthony S. Fauci, Stephen L. Hauser, and Joseph Loscalzo. Harrison’s Principles of Internal Medicine (18 ed.). McGraw-Hill.
Rhoades, Rodney (2009). Medical Physiology: Principles for Clinical Medicine. Philadelphia: Lippincott Williams & Wilkins. ISBN 978-0-7817-6852-8.
Jump up^ Carney SL (1997). “Calcitonin and human renal calcium and electrolyte transport”.Miner Electrolyte Metab 23 (1): 43–7. PMID 9058369.
Jump up^ Nicholson GC, Moseley JM, Sexton PM, et al (1986). “Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization”. J Clin Invest 78 (2): 355–60. doi:10.1172/JCI112584. PMC 423551. PMID 3016026.
Jump up^ Copp DH, Cheney B (January 1962). “Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood”. Nature 193 (4813): 381–2.doi:10.1038/193381a0. PMID 13881213.
Jump up^ Hirsch PF, Gauthier GF, Munson PL (August 1963). “Thyroid hypocalcemic principle and recurrent laryngeal nerve injury as factors affecting the response to parathyroidectomy in rats”. Endocrinology 73 (2): 244–252. doi:10.1210/endo-73-2-244.PMID 14076205.
Jump up^ Wall GC, Heyneman CA (April 1999). “Calcitonin in phantom limb pain”. Ann Pharmacother 33 (4): 499–501. doi:10.1345/aph.18204. PMID 10332543.
Jump up^ Tran de QH, Duong S, Finlayson RJ (July 2010). “Lumbar spinal stenosis: a brief review of the nonsurgical management”. Can J Anaesth 57 (7): 694–703. doi:10.1007/s12630-010-9315-3. PMID 20428988.
^ Jump up to:^a ^b “Electronic Medicines Compendium”. Retrieved 2008-08-07.
Jump up^ Kleinman DM (2006-01-04). “Oral Calcitonin May Delay Onset of Joint Disease and Relieve Pain of OA”. Musculoskeletal Report. Musculoskeletal Report, LLC. Retrieved 2008-08-07.
Jump up^ Vik A, Yatham LN (March 1998). “Calcitonin and bipolar disorder: a hypothesis revisited”. J Psychiatry Neurosci 23 (2): 109–17. PMC 1188909. PMID 9549251.
Jump up^ Basuyau, J. -P.; Mallet, E.; Leroy, M.; Brunelle, P. (2004). “Reference Intervals for Serum Calcitonin in Men, Women, and Children”. Clinical Chemistry 50 (10): 1828–1830.doi:10.1373/clinchem.2003.026963. PMID 15388660. edit
Jump up^ Burtis CA, Ashwood ER, Bruns DE. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th edition. Elsevier Saunders. p. 1774. ISBN 978-1-4160-6164-9.
Jump up^ “calcitonin domain annotation”. SMART (a Simple Modular Architecture Research Tool). embl-heidelberg.de. Retrieved 2009-02-22.
Jump up^ http://www.newworldencyclopedia.org/entry/Calcitonin

External links

The Calcitonin Protein
Calcitonin at the US National Library of Medicine Medical Subject Headings (MeSH)

Literature References:

Calcium regulating hormone secreted from the mammalian thyroid gland and in non-mammalian species from the ultimobranchial gland. Postulation of a plasma-calcium lowering substance: Copp et al., Endocrinology 70, 638 (1962).

Recognition as a hormone: Hirsch et al., ibid. 73, 244 (1963); of thyroid origin: Foster et al., Nature 202, 1303 (1964).

Over-all action is to oppose the bone and renal effects of parathyroid hormone, q.v.; inhibits bone resorption of Ca2+, with accompanying hypocalcemia and hypophosphatemia and decreased urinary Ca2+ concentrations. Also abolishes the osteolytic effect of toxic doses of vitamins A and D. Calcitonin is highly active biologically, e.g. 50 mg/min infused into a 100 g rat leads to a significant (1 mg/100 ml) decrease in the concn of the plasma calcium within 60 min (together with a corresponding fall in plasma phosphate). Activity is destroyed by trypsin, chymotrypsin, pepsin, polyphenol oxidase; also by hydrogen peroxide oxidation, photooxidation, and treatment with N-bromosuccinimide. Calcitonin structures are single polypeptide chains containing 32 amino acid residues. Structure of porcine: Neher et al., Helv. Chim. Acta 51, 917 (1968); Potts et al., Proc. Natl. Acad. Sci. USA 59, 1321 (1968); Bellet al., J. Am. Chem. Soc. 90, 2704 (1968); eidem, Biochemistry 9, 1665 (1970).

Synthesis of porcine: Rittel et al., Helv. Chim. Acta 51, 924 (1968); Guttmann et al., ibid. 1155.

Isoln of human calcitonin from non-pathological thyroid glands: Haymovits, Rosen, Endocrinology 81, 993 (1967); from medullary carcinoma of the thyroid: Neher et al., Nature 220, 984 (1968); Helv. Chim. Acta 51, 1738 (1968); Neher, Riniker, DE 1929957 (1970 to Ciba), C.A. 73, 28902b (1970).

Structure of human: Neher et al., Helv. Chim. Acta 51, 1900 (1968). Synthesis of human: Sieber et al., ibid. 2057; J. Hirt et al., Rec. Trav. Chim. 98, 143 (1979).

Biosynthetic studies: J. W. Jacobs et al., J. Biol. Chem. 254, 10600 (1979); S. G. Amara et al., ibid. 255, 2645 (1980).

Amino acid sequence differs among mammalian species, salmon calcitonin showing a marked difference from that of the higher vertebrae as well as a more potent biological activity. Mechanism of action: E. M. Brown, G. D. Aurbach, Vitam. Horm. 38, 236 (1980). Anorectic activity in rats: W. J. Freed et al., Science 206, 850 (1979).

Growth inhibition of human breast cancer cells in vitro: Y. Iwasaki et al., Biochem. Biophys. Res. Commun. 110, 235 (1983).

Review of early literature: Munson, Hirsch, Clin. Orthop. 49, 209 (1966).

Review of isoln, structure, synthesis: Behrens, Grinnan, Annu. Rev. Biochem. 38, 83 (1969); Potts et al., Vitam. Horm. 29,41 (1971).

Comprehensive review: Calcitonin, Proc. Symp. on Thyrocalcitonin and the C Cells, S. Taylor, Ed. (Springer-Verlag, New York, 1968); Foster et al., ”Calcitonin” in Clinics in Endocrinology and Metabolism, I. MacIntyre, Ed. (W. B. Saunders, Philadelphia, 1972) pp 93-124.

Review of pharmacology and therapeutic use: J. C. Stevenson, I. M. A. Evans, Drugs 21, 257-272 (1981).

Derivative Type: Calcitonin, porcine

CAS Registry Number: 12321-44-7

Trademarks: Calcitar(e) (RPR); Staporos (Cassenne)

Derivative Type: Calcitonin, human synthetic

CAS Registry Number: 21215-62-3

Trademarks: Cibacalcin (Novartis)

Derivative Type: Calcitonin, salmon synthetic

CAS Registry Number: 47931-85-1

Additional Names: Salcatonin

Trademarks: Calciben (Firma); Calcimar (RPR); Calsyn (RPR); Calsynar (RPR); Catonin (Magis); Karil (Novartis); Miacalcic (Novartis); Miacalcin (Novartis); Miadenil (Francia); Osteocalcin (Tosi); Prontocalcin (Domp?; Rulicalcin (HMR); Salmotonin (Yamanouchi); Stalcin (Locatelli); Tonocalcin (Searle)

Literature References: Clinical trial in postmenopausal osteoporosis: C. H. Chesnut et al., Am. J. Med. 109, 267 (2000). LC determn in biological fluids: M. Aguiar et al., J. Chromatogr. B 818, 301 (2005).

Properties: See also Elcatonin.

eel

cas 57014-02-5

Directing Venom To Fight Cancer ACS Meeting News: Encapsulated venom peptide can skip healthy cells

August 18, 2014 7:20 am / Leave a comment

ORGANIC CHEMISTRY SELECT

09233-notw11-scorpioncxd

Scorpion toxins may one day be useful as anticancer drugs.

Credit: Courtesy of Dipanjan Pan

Venom from scorpions or honeybees sounds like it wouldn’t do a person much good. But by directing a modified component just to tumors, researchers might leverage it into a drug.

Peptides in some venoms bind to cancer cells and block tumor growth and spread. But they have not yet been developed successfully as anticancer agents because they attack healthy cells too.

Bioengineer Dipanjan Pan and coworkers at the University of Illinois, Urbana-Champaign, are now using polymeric nanoparticles to deliver venom toxin directly to cancer cells.

read at

http://cen.acs.org/articles/92/i33/Directing-Venom-Fight-Cancer.html

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WHO issues draft proposal for biosimilar naming

August 18, 2014 7:13 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

biosimilar ladder WHO issues draft proposal for biosimilar naming

A long debate is ongoing about biosimilar naming around the world. Although EU accepted the same INN system years ago, with the latest developments around the world, biosimilar naming uncertainty is still ongoing.

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Neuroprotective effects of Asiaticoside – a Saponin of Centella asiatica

August 17, 2014 3:13 am / Leave a comment

CLINICALNEWS.ORG

PUBLIC RELEASE DATE:

10-Aug-2014

In the central nervous system, Asiaticoside has been shown to attenuate in vitro neuronal damage caused by exposure to β-amyloid. However, its potential neuroprotective properties in glutamate-induced excitotoxicity have not been fully studied. Researchers from Fourth Military Medical University of Chinese PLA, China reported that pretreatment with Asiaticoside decreased neuronal cell loss in a concentration-dependent manner and restored changes in expression of apoptotic-related proteins Bcl-2 and Bax. Asiaticoside pretreatment also attenuated the upregulation of NR2B expression, a subunit of N-methyl-D-aspartate receptors, but did not affect expression of NR2A subunits. Additionally, in cultured neurons, Asiaticoside significantly inhibited Ca2+ influx induced by N-methyl-D-aspartate. Their results provide a new insight into the neuroprotective effects of Asiaticoside. The relevant study has been published in the Neural Regeneration Research (Vol. 9, No. 13, 2014).

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Lipid Metabolism

August 17, 2014 3:10 am / Leave a comment

Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Lipid metabolism

Larry H. Bernstein, MD, FCAP, Reporter and Curator

Leaders in Pharmaceutical Intelligence

http://pharmaceuticalintelligence.com/8-10-2014/Lipid_metabolism

This is fourth of a series of articles, lipid metabolism, that began with signaling and signaling pathways. These discussion lay the groundwork to proceed in later discussions that will take on a somewhat different approach. These are critical to develop a more complete point of view of life processes. I have indicated that many of the protein-protein interactions or protein-membrane interactions and associated regulatory features have been referred to previously, but the focus of the discussion or points made were different. The role of lipids in circulating plasma proteins as biomarkers for coronary vascular disease can be traced to the early work of Frederickson and the classification of lipid disorders. The very critical role of lipids in membrane structure in health and disease has had much less attention, despite the enormous importance, especially in…

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Macrocycles in new drug discovery

August 15, 2014 2:33 pm / 1 Comment on Macrocycles in new drug discovery

Macrocycles in new drug discovery

Jamie Mallinson, Ian Collins

Future Medicinal Chemistry, Jul 2012, Vol. 4, No. 11, Pages 1409-1438.

http://www.future-science.com/doi/full/10.4155/fmc.12.93?src=recsys

The use of drug-like macrocycles is emerging as an exciting area of medicinal chemistry, with several recent examples highlighting the favorable changes in biological and physicochemical properties that macrocyclization can afford. Natural product macrocycles and their synthetic derivatives have long been clinically useful and attention is now being focused on the wider use of macrocyclic scaffolds in medicinal chemistry in the search for new drugs for increasingly challenging targets. With the increasing awareness of concepts of drug-likeness and the dangers of ‘molecular obesity’, functionalized macrocyclic scaffolds could provide a way to generate ligand-efficient molecules with enhanced properties. In this review we will separately discuss the effects of macrocyclization upon potency, selectivity and physicochemical properties, concentrating on recent case histories in oncology drug discovery. Additionally, we will highlight selected advances in the synthesis of macrocycles and provide an outlook on the future use of macrocyclic scaffolds in medicinal chemistry.

Carbohydrate Metabolism

August 15, 2014 1:41 am / Leave a comment

Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Carbohydrate Metabolism

Larry H. Bernstein, MD, FCAP, Reporter and Curator

Leaders in Pharmaceutical Intelligence

http://pharmaceuticalintelligence.com/8-9-2014/Carbohydrate_Metabolism

This is the third portion of the discussion in a series of articles that began with signaling and signaling pathways. There are fine features on the functioning of enzymes and proteins, on sequential changes in a chain reaction, and on conformational changes that we shall return to. These are critical to developing a more complete understanding of life processes. I have indicated that many of the protein-protein interactions or protein-membrane interactions and associated regulatory features have been referred to previously, but the focus of the discussion or points made were different. Even though I considered placing this after the discussion of proteins and how they play out their essential role, I needed to lay out the scope of metabolic reactions and pathways, and their complementary changes. These may not appear to be adaptive, if the…

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Ebola – What’s the Pipeline?

August 15, 2014 1:38 am / Leave a comment

Valdecoxib

August 14, 2014 12:37 pm / 1 Comment on Valdecoxib

Valdecoxib

CAS Registry Number: 181695-72-7

4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide

Manufacturers’ Codes: SC-65872

Bextra (Pharmacia & Upjohn)

Molecular Formula: C16H14N2O3S

Molecular Weight: 314.36

Percent Composition: C 61.13%, H 4.49%, N 8.91%, O 15.27%, S 10.20%

Properties: Crystals, mp 155-157°. Soly at 25°(mg/ml): water 10 (pH 7.0). Sol in methanol, ethanol; freely sol in organic solvents and alkaline (pH = 12) aqueous solns.

Melting point: mp 155-157°

Therap-Cat: Anti-inflammatory; analgesic

Valdecoxib is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, and painfulmenstruation and menstrual symptoms. It is a cyclooxygenase-2 selective inhibitor.

Valdecoxib was manufactured and marketed under the brand name Bextra by G. D. Searle & Company. It was approved by the United States Food and Drug Administration on November 20, 2001,^[1] and was available by prescription in tablet form until 2005, when it was removed from the market due to concerns about possible increased risk of heart attack and stroke. The prodrugparecoxib is available in many countries.

Uses until 2005

In the United States, the Food and Drug Administration (FDA) approved valdecoxib for the treatment of osteoarthritis, adultrheumatoid arthritis, and primary dysmenorrhea.^[2]

Valdecoxib was also used off-label for controlling acute pain and various types of surgical pain.^[2]

Side-effects and withdrawal from market

On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA, citing an increased risk of heart attackand stroke and also the risk of a serious, sometimes fatal, skin reaction. This was a result of recent attention to prescription NSAIDs, such as Merck’s Vioxx. Other reported side-effects were angina and Stevens–Johnson syndrome.

Pfizer first acknowledged cardiovascular risks associated with Bextra in October 2004. The American Heart Association soon after was presented with a report indicating patients using Bextra while recovering from heart surgery were 2.19 times more likely to suffer a stroke or heart attack than those taking placebos.

In a large study published in JAMA 2006, valdecoxib appeared less adverse for renal (kidney) disease and heart arrhythmia compared to Vioxx, however elevated renal risks were slightly suggested.^[3]

2009 settlement for off-label uses promotions

An editor has expressed a concern that this section lends undue weight to certain ideas relative to the article as a whole. Please help to discuss and resolve the dispute before removing this message. (December 2012)

On September 2, 2009, the United States Department of Justice fined Pfizer $2.3 billion after one of its subsidiaries, Pharmacia & UpJohn Company, pled guilty to marketing four drugs including Bextra “with the intent to defraud or mislead.”^[4] Pharmacia & UpJohn admitted to criminal conduct in the promotion of Bextra, and agreed to pay the largest criminal fine ever imposed in the United States for any matter, $1.195 billion.^[5] A former Pfizer district sales manager was indicted and sentenced to home confinement for destroying documents regarding the illegal promotion of Bextra.^[6]^[7] In addition, a Regional Manager pled guilty to distribution of a mis-branded product, and was fined $75,000 and twenty-four months on probation.^[8]

The remaining $1 billion of the fine was paid to resolve allegations under the civil False Claims Act case and is the largest civil fraud settlement against a pharmaceutical company. Six whistle-blowers were awarded more than $102 million for their role in the investigation.^[9] Former Pfizer sales representative John Kopchinski acted as a qui tam relator and filed a complaint in 2004 outlining the illegal conduct in the marketing of Bextra.^[10] Kopchinski was awarded $51.5 million for his role in the case because the improper marketing of Bextra was the largest piece of the settlement at $1.8 billion.^[11]

Assay of Valdecoxib^[13]

Several HPLC-UV methods have been reported for valdecoxib estimation in biological samples like human urine,^[14] plasma,.^[15]^[16] Valdecoxib has analytical methods for bioequivalence studies,^[17]^[18] metabolite determination,^[19]^[20]^[21] and estimation of formulation,^[22] HPTLC method for simultaneous estimation in tablet dosage form.^[23]

Brief background information

Salt	ATC	Formula	MM	CAS
–	M01AH03	C ₁₆ H ₁₄ N ₂ O ₃ S	314.37 g / mol	181695-72-7

Systematic (IUPAC) name
4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide
Clinical data
Trade names	Bextra
Pregnancy cat.	C (AU) May cause premature closure of the ductus arteriosus
Legal status	Prescription Only (S4) (AU)Withdrawn in U.S., EU, Canada& parts of Asia
Routes	Oral
Pharmacokinetic data
Bioavailability	83%
Protein binding	98%
Metabolism	Hepatic (CYP3A4 and 2C9involved)
Half-life	8 to 11 hours
Excretion	Renal
Identifiers
CAS number	181695-72-7
ATC code	M01AH03
PubChem	CID 119607
DrugBank	DB00580
ChemSpider	106796
UNII	2919279Q3W
KEGG	D02709
ChEBI	CHEBI:63634
ChEMBL	CHEMBL865
Chemical data
Formula	C₁₆H₁₄N₂O₃S
Mol. mass	314.364 g/mol

Using

anti-inflammatory
antirheumatic
COX-2 inhibitor

Classes of substances

Benzenesulfonamide (s -imidy), as well as their derivatives
- Isoxazoles

Synthesis pathway

Synthesis a)

Synthesis

Source:^[12]

Deoxybenzoin (I) is converted to the corresponding oxime (II) by treatment with NH2OH稨Cl under basic conditions either with sodium acetate in aqueous ethanol or in toluene in presence of potassium hydroxide in absolute ethanol. Deprotonation of the oxime under nitrogen with 2eq of butyllithium in THF followed by cyclization in ethyl acetate or acetic anhydride affords isoxazoline (III). Finally, treatment of (III) with cold chlorosulfonic acid followed by reaction of the intermediate sulfonyl chloride with aqueous ammonia affords the desired product.

J Med Chem2000,43,(5):775

Trade Names

Country	Trade name	Manufacturer
Germany	Bextra	Pharmacia
USA	– “-	– “-
Ukraine	No	No

Formulations

Tablets of 10 mg, 20 mg

Valdecoxib is chemically designated as 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide and is a diaryl substituted isoxazole.

The empirical formula for valdecoxib is C₁₆H₁₄N₂O₃S, and the molecular weight is 314.36. Valdecoxib is a white crystalline powder that is relatively insoluble in water (10 µg/mL) at 25° C and pH 7.0, soluble in methanol and ethanol, and freely soluble in organic solvents and alkaline (pH=12) aqueous solutions.

BEXTRA (valdecoxib) Tablets for oral administration contain either 10 mg or 20 mg of valdecoxib. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium,magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide

………………………

NMR

Links

Talley, JJ et al .: J. Med. Chem. (JMCMAR) 43, 775-777 (2000).
US 5,859,257 (GD Searle; 12.1.1999; USA-prior. 13.2.1995).

Literature References:

Selective cyclooxygenase-2 (COX-2) inhibitor. Active metabolite of parecoxib, q.v. Prepn: J. J. Talley et al., WO 9625405 (1996 to Searle); eidem, US 5633272 (1997); and activity: eidem, J. Med. Chem. 43, 775 (2000).

Chromatographic determn of purity: D. A. Roston et al., J. Pharm. Biomed. Anal. 26, 339 (2001).

Gastrointestinal tolerability study: G. M. Eisen et al., Aliment. Pharmacol. Ther. 21, 591 (2005).

Clinical trial in hip arthroplasty: F. Camu et al., Am. J. Ther.9, 43 (2002).

Clinical comparison with oxycodone/acetominophen in dental pain: S. E. Daniels et al., J. Am. Dent. Assoc. 133, 611 (2002).

Clinical trial in migraine: D. Kudrow et al., Headache 45, 1151 (2005).

Review of clinical experience: M. Goldman, S. Schutzer, Formulary 37, 68-77 (2002); of clinical efficacy and safety: G. P. Joshi, Expert Rev. Neurother. 5, 11-24 (2005).

References

Jump up^ Thomson Micromedex. “Valdecoxib. U.S. FDA Drug Approval.” Last accessed June 8, 2007.
^ Jump up to:^a ^b “Pfizer to pay $2.3 billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks”. Stop Medicare Fraud, US Dept of Health & Human Svc, and of Justice. Retrieved 2012-07-04.
Jump up^ “Adverse Effects of Cyclooxygenase-2 Inhibitors on Renal and Arrhythmia Events: Meta-Analysis of Randomized Trials”, (JAMA 2006, by Zhang JJ, Ding EL, Song Y.).
Jump up^ http://news.bbc.co.uk/2/hi/business/8234533.stm Pfizer agrees record fraud fine
Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/Sept2009/PharmaciaPlea.html
Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/Mar2009/FarinaconvictionPR.html
Jump up^ http://industry.bnet.com/pharma/10002882/pfizers-off-label-bextra-team-were-called-the-highlanders/
Jump up^ http://www.usdoj.gov/usao/ma/Press%20Office%20-%20Press%20Release%20Files/June2009/HollowayMarySentencingPR.html
Jump up^ http://www.fbi.gov/pressrel/pressrel09/justice_090209.htm
Jump up^ http://www.phillipsandcohen.com/CM/NewsSettlements/NewsSettlements536.asp
Jump up^ http://www.phillipsandcohen.com/CM/NewsSettlements/NewsSettlements531.asp
Jump up^ Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. (2000). “4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, Valdecoxib: A Potent and Selective Inhibitor of COX-2”. Journal of Medicinal Chemistry 43 (5): 775–777. doi:10.1021/jm990577v.PMID 10715145. edit
Jump up^ Prafulla Kumar Sahu and M. Mathrusri Annapurna, Analytical method development by liquid chromatography, LAP Lambert Academic Publisher, Germany, 2011 ISBN 3-8443-2869-6.
Jump up^ Zhang J Y, Fast D M and Breau A P, J Chromatogr B Analyt Technol Biomed Life Sci., 2003, 785(1), 123-134
Jump up^ Ramakrishna N V S, Vishwottam K N; Wishu S and Koteshwara M, J Chromatogr B Analyt Technol Biomed Life Sci., 2004, 802(2), 271.
Jump up^ Sane R T, Menon S, Deshpande A Y and Jain A, Chromatogr., 2005, 61(3-4), 137-141.
Jump up^ Prafulla Kumar Sahu*, K. Ravi Sankar and M. Mathrusri Annapurna, Determination of Valdecoxib in human plasma using Reverse Phase HPLC”, E-Journal of Chemistry, 2011, 8(2), 875-881.
Jump up^ Mandal U, Jayakumar M, Ganesan M, Nandi S, Pal T K, Chakraborty M K, Roy Chowdhary A. and Chattoraj T K, Indian Drugs, 2004, 41, 59.
Zhang J.Y, Fast D.M and Breau, A.P, J Pharm Biomed Anal., 2003, 33, 61.
Werner U, Werner D, Hinz B, Lanbrecht C and Brune K, J Biomed Chromatogr., 2004, 19, 113.
Zhang J V, Fast D M and Breau A P, J Chromatogr B Anal Technol Biomed Life Sci., 2003, 785, 123.
Sutariya V B, Rajashree M, Sankalia M G. and Priti P, Indian J Pharm Sci., 2004, 93, 112.
J Gandhimathi M, Ravi T K, Shukla Nilima and Sowmiya G, Indian J Pharm Sci., 2007, 69(1), 145-147.

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The structural formula

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IR – spectrum

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Uses until 2005

Side-effects and withdrawal from market

2009 settlement for off-label uses promotions

Assay of Valdecoxib[13]

Brief background information

Using

Classes of substances

Synthesis pathway

Synthesis

Trade Names

Formulations

Links

References

External links[edit]

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Assay of Valdecoxib^[13]