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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 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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Temanogrel

June 13, 2016 4:08 am / Leave a comment


ChemSpider 2D Image | temanogrel | C24H28N4O4TEMANOGREL.pngimg

Temanogrel

APD 791

3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholinoethoxy)phenyl]benzamide
Benzamide,3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-
UNII:F42Z27575A
TEMANOGREL; APD791; CHEMBL1084617; UNII-F42Z27575A; 887936-68-7; 3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;
Molecular Formula: C24H28N4O4
Molecular Weight: 436.50352 g/mol
  • Originator Arena Pharmaceuticals
  • Developer Arena Pharmaceuticals; Ildong Pharmaceutical
  • Class Antithrombotics; Small molecules
  • Mechanism of Action Serotonin 2A receptor inverse agonists

Phase I Arterial thrombosis

Most Recent Events

  • 30 Mar 2016 Arena Pharmaceuticals has patents pending for Temanogrel in 12 regions, including Brazil (Arena Pharmaceuticals 10-K; march 2016)
  • 30 Mar 2016 Arena Pharmaceuticals has patent protection for Temanogrel in 87 regions, including USA, Japan, China, Germany, France, Italy, the United Kingdom, Spain, Canada, Russia, India, Australia and South Korea
  • 01 Mar 2015 Ildong Pharmaceutical initiates enrolment in a phase I trial for Arterial thrombosis in South Korea (NCT02419820)

A 5-HT2A inverse agonist potentially for the reduction of the risk of arterial thrombosis.

APD-791

CAS No. 887936-68-7

ChemSpider 2D Image | Temanogrel hydrochloride | C24H29ClN4O4

Temanogrel hydrochloride

  • Molecular FormulaC24H29ClN4O4
  • Average mass472.965
957466-27-2 CAS
Benzamide, 3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-, hydrochloride (1:1) [ACD/Index Name]
Temanogrel hydrochloride [USAN]
UNII:5QEY8NZP3T

Temanogrel, also known as APD791, is a highly selective 5-hydroxytryptamine2A receptor inverse agonist under development for the treatment of arterial thrombosis. APD791 displayed high-affinity binding to membranes (K(i) = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC(50) = 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT(2A) receptor. APD791 was greater than 2000-fold selective for the 5-HT(2A) receptor versus 5-HT(2C) and 5-HT(2B) receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC(50) = 8.7 and 23.1 nM, respectively)

Arterial thrombosis is the formation of a blood clot or thrombus inside an artery or arteriole that restricts or blocks the flow of blood and, depending upon location, can result in acute coronary syndrome or stroke. The formation of a thrombus is usually initiated by blood vessel injury, which triggers platelet aggregation and adhesion of platelets to the vessel wall. Treatments aimed at inhibiting platelet aggregation have demonstrated clear clinical benefits in the setting of acute coronary syndrome and stroke. Current antiplatelet therapies include aspirin, which irreversibly inhibits cyclooxygenase (COXa

Abbreviations: COX, cyclooxygenase; ADP, adenosine diphosphate; SAR, structure−activity relationship; hERG, human ether-a-go-go-related gene; CNS, central nervous system; 5-HT, serotonin; AUC, area under the plasma concentration time curve, iv, intravenous; IP, inositol phosphate.

) and results in reduced thromboxane production, clopidogrel and prasugrel, which inhibit platelet adenosine diphosphate (ADP) P2Y12 receptors, and platelet glycoprotein IIb/IIIa receptor antagonists. Another class of antiplatelet drugs, protease-activated thrombin receptor (PAR-1) antagonists, are also being evaluated in the clinic for the treatment of acute coronary syndrome. The most advanced candidate in this class, N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1-methyl-3-oxoperhydro-naphtho[2,3-c]furan-6-yl]-carbamic acid ethyl ester (SCH-530348), is currently in phase 3 trials for the prevention of arterial thrombosis.

The 5-HT2A receptor is one of 15 different serotonin receptor subtypes.
 In the cardiovascular system, modulation of 5-HT2A receptors on vascular smooth muscle cells and platelets is thought to play an important role in the regulation of cardiovascular function. Platelets are activated by a variety of agonists such as ADP, thrombin, thromboxane, serotonin, epinephrine, and collagen. Upon platelet activation at the site of blood vessel injury, a number of factors including serotonin (5-HT) are released. Although by itself serotonin is a weak activator of platelet aggregation, in vitro it can amplify aggregation induced by other agonists as mentioned above. Therefore, serotonin released from activated platelets may induce further platelet aggregation and enhance thrombosis.
The 5-HT2A receptor antagonist ketanserin  was shown in clinical studies to reduce early restenosis(7) and decrease myocardial ischemia during coronary balloon angioplasty.(8)However, in another study, ketanserin did not significantly improve clinical outcomes, and the rate of adverse events was higher than that observed in the control group.(9) Some of the adverse events reported in the latter study could be specific to ketanserin and resulted from its lack of 5-HT2A receptor selectivity. Other 5-HT2A antagonists with improved selectivity profiles have shown promise in clinical studies. For example, sarpogrelate  was shown to inhibit restenosis following coronary stenting.

Figure

Figure 1. Serotonin and known 5-HT2A receptor antagonists.

Because the 5-HT2A receptor is expressed both in peripheral tissues and in the central nervous system (CNS), compounds with limited CNS partitioning would be preferred to maximize cardiovascular and blood platelet pharmacological activity while minimizing CNS effects. In addition, because 5-HT2A receptor inverse agonists are thought to reduce thrombus formation via inhibition of serotonin-mediated amplification of platelet aggregation without inhibiting agonist driven aggregation per se, it is possible that this class of inhibitors will have an improved bleeding risk side effect profile compared to what has been observed with other classes of antithrombotic drugs.

SYNTHESIS 

PAPER

Journal of Medicinal Chemistry (2010), 53(11), 4412-4421.

http://pubs.acs.org/doi/abs/10.1021/jm100044a

Abstract Image

Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121
J. Med. Chem., 2010, 53 (11), pp 4412–4421
DOI: 10.1021/jm100044a
Publication Date (Web): May 10, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: +1 858-453-7200. Fax: +1 858-453-7210. E-mail:yxiong@arenapharm.com.

3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (10k)

10k was prepared in a manner similar to that described for 10c, using 9d (120 mg, 0.40 mmol) and 3-methoxybenzoyl chloride (81 mg, 0.48 mmol) to give the TFA salt of 10k as a white solid (88 mg, 51%); mp (HCl salt, recrystallized from iPrOH) 214−216 °C. 1H NMR (acetone-d6, 400 MHz) δ: 2.99−3.21 (m, 2H), 3.22−3.45 (m, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79−3.89 (m, 4H), 4.58 (t, J = 4.8 Hz, 2H), 6.29 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.5, 8.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.52 (t, J = 1.7 Hz, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.80−7.83 (m, 1H), 7.91−7.96 (m, 1H), 9.54 (s, 1H). LCMSm/z = 437.5 [M + H]+.

Additional Information

Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT(2A) receptor antagonist with potent activity on platelets and vascular smooth muscle.(http://www.ncbi.nlm.nih.gov/pubmed/19628629).

 

PATENT

WO 2006055734

https://google.com/patents/WO2006055734A2?cl=en

Example 1.88: Preparation of 3-methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin~

4-yl-ethoxy)-phenyl]-benzamide (Compound 733).

Figure imgf000151_0002

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole), and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 88 mg, 51 %). 1H NMR ( Acetone-^, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, J= 4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t, J= 4.80 Hz, 2H), 6.29 (d, J= 2.02 Hz IH), 7.13 (dd, J= 8.34, 2.53 Hz, IH), 7.22 (d, J= 8.84 Hz, IH), 7.42 (t, J= 7.83 Hz, IH), 7.47 (d, J= 1.77 Hz, IH), 7.52 (t, J= 1.77 Hz, IH), 7.56 (d, J= 7.07 Hz, IH), 7.80-7.83 (m, IH), 7.91-7.96 (m, IH), 9.54 (s, NH). Exact mass calculated for C24H28N4O4 436.2, found 437.5 (MH+).

References

1: Xiong Y, Teegarden BR, Choi JS, Strah-Pleynet S, Decaire M, Jayakumar H, Dosa
PI, Casper MD, Pham L, Feichtinger K, Ullman B, Adams J, Yuskin D, Frazer J,
Morgan M, Sadeque A, Chen W, Webb RR, Connolly DT, Semple G, Al-Shamma H.
Discovery and structure-activity relationship of
3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide
(APD791): a highly selective 5-hydroxytryptamine2A receptor inverse agonist for
the treatment of arterial thrombosis. J Med Chem. 2010 Jun 10;53(11):4412-21.
doi: 10.1021/jm100044a. PubMed PMID: 20455563.

2: Przyklenk K, Frelinger AL 3rd, Linden MD, Whittaker P, Li Y, Barnard MR, Adams
J, Morgan M, Al-Shamma H, Michelson AD. Targeted inhibition of the serotonin
5HT2A receptor improves coronary patency in an in vivo model of recurrent
thrombosis. J Thromb Haemost. 2010 Feb;8(2):331-40. doi:
10.1111/j.1538-7836.2009.03693.x. Epub 2009 Nov 17. PubMed PMID: 19922435; PubMed
Central PMCID: PMC2916638.

3: Adams JW, Ramirez J, Shi Y, Thomsen W, Frazer J, Morgan M, Edwards JE, Chen W,
Teegarden BR, Xiong Y, Al-Shamma H, Behan DP, Connolly DT. APD791,
3-methoxy-n-(3-(1-methyl-1h-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide,
a novel 5-hydroxytryptamine 2A receptor antagonist: pharmacological profile,
pharmacokinetics, platelet activity and vascular biology. J Pharmacol Exp Ther.
2009 Oct;331(1):96-103. doi: 10.1124/jpet.109.153189. Epub 2009 Jul 23. PubMed
PMID: 19628629.

Patent ID Date Patent Title
US2015361031 2015-12-17 STAT3 INHIBITOR
US8785441 2014-07-22 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US2013296321 2013-11-07 CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF PHENYL-PYRAZOLES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
US2012252813 2012-10-04 CRYSTALLINE FORMS OF CERTAIN 3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148417 2012-04-03 PRIMARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148418 2012-04-03 ETHERS, SECONDARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US2011105456 2011-05-05 3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US7884101 2011-02-08 3-Phenyl-pyrazole derivatives as modulators of the 5-HT2a serotonin receptor useful for the treatment of disorders related thereto
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///////////APD-791 , 887936-68-7, Temanogrel , PHASE 1, ARENA,

CN1C(=CC=N1)C2=C(C=CC(=C2)NC(=O)C3=CC(=CC=C3)OC)OCCN4CCOCC4

C(=O)(c1cc(ccc1)OC)Nc1ccc(c(c1)c1n(ncc1)C)OCCN1CCOCC1

Arena Pharmaceuticals Initiates Phase 1 Clinical Trial of APD334 for Autoimmune Diseases

April 8, 2013 3:16 am / 1 Comment on Arena Pharmaceuticals Initiates Phase 1 Clinical Trial of APD334 for Autoimmune Diseases


April 5, 2013

Arena Pharmaceuticals, Inc.  announced today the initiation of dosing in a Phase 1 clinical trial of APD334, a novel oral drug candidate that targets the sphingosine 1-phosphate subtype 1 (S1P1) receptor for the potential treatment of autoimmune diseases.

This randomized, double-blind and placebo-controlled Phase 1 trial will evaluate the safety, tolerability and pharmacokinetics of single-ascending doses of APD334 in up to 64 healthy adult volunteers.

“We are pleased to expand our clinical-stage pipeline by initiating a Phase 1 trial of APD334, and look forward to advancing this novel compound through our validated development platform,” said William R. Shanahan, M.D., Arena’s Senior Vice President and Chief Medical Officer. “APD334’s selectivity for the S1P1 receptor has the potential to improve upon the adverse event profile of currently available treatments for a spectrum of autoimmune diseases.”

About Autoimmune Diseases

Autoimmune diseases are characterized by an inappropriate immune response against substances and tissues that are normally present in the body. In an autoimmune reaction, a person’s antibodies and immune cells target healthy tissues, triggering an inflammatory response. Reducing the immune and/or inflammatory response is an important goal in the treatment of autoimmune disease.

About APD334

APD334 is an orally available drug candidate discovered by Arena that targets the S1P1 receptor for the potential treatment of a number of conditions related to autoimmune diseases, including multiple sclerosis, psoriasis and rheumatoid arthritis. S1P1 receptors have been demonstrated to be involved in the modulation of several biological responses, including lymphocyte trafficking from lymph nodes to the peripheral blood. By isolating lymphocytes in lymph nodes, fewer immune cells are available in the circulating blood to effect tissue damage. Arena has optimized APD334 as a potent and selective small molecule S1P1 receptor agonist that reduces the severity of disease in preclinical autoimmune disease models.

About Arena Pharmaceuticals

Arena is a biopharmaceutical company focused on discovering, developing and commercializing novel drugs that target G protein-coupled receptors, or GPCRs, to address unmet medical needs. BELVIQ® (lorcaserin HCl), Arena’s internally discovered drug, was approved by the US Food and Drug Administration in June 2012 and is under review for regulatory approval in additional territories. Arena’s US operations are located in San Diego, California, and its operations outside of the United States, including its commercial manufacturing facility, are located in Zofingen, Switzerland. For more information, visit Arena’s website at www.arenapharm.com.

Arena Pharmaceuticals® and Arena® are registered service marks of Arena Pharmaceuticals, Inc. BELVIQ® is a registered trademark of Arena Pharmaceuticals GmbH

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