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AZD 2716

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AZD2716

CAS 1845753-81-2
MF C24 H23 N O3,   MW 373.44
[1,1′-Biphenyl]-3-propanoic acid, 2′-(aminocarbonyl)-α-methyl-5′-(phenylmethyl)-, (αR)-
Antiplaque candidate drug

AstraZeneca INNOVATOR

(R)-7(AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Chiral HPLC using a Chiralcel OJ 5 μm 20×250 mm
column with heptane/EtOH/formic acid ((10:90:0.1; 15 ml/min, 40 °C, 260 nm) as mobile
phase to yield (S)-7 and (R)-7

(R)-7:tR=5.8 min [α]D20 15.4 (c 0.5, ACN), 99.7 %ee. desired

(S)-7: tR=9.2 min. 99.0 % ee. undesired

LINK

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00188

SYNTHESIS

 

op-2015-00382y_0007.gif

1H NMR (400 MHz, DMSO-d6): δ 1.04 (d, J = 6.6 Hz, 3H), 2.55–2.68 (m, 2H), 2.95 (dd, J = 6.1, 12.8 Hz, 1H), 4.00 (s, 2H), 7.13–7.37 (m, 13H), 7.49–7.54 (m, 1H), 12.2 (s, br, 1H).

13C NMR (151 MHz, DMSO): δ 16.7, 39.1, 40.7, 41.0, 126.3, 126.4, 127.3, 127.8, 128.0, 128.2, 128.7, 128.9, 129.2, 130.3, 135.3, 139.2, 139.5, 140.5, 141.2, 142.7, 171.3, 177.1.

HRMS (ESI): [M + H]+ m/z calcd for C24H24NO3 374.1751, found 374.1748.

1H NMR

 

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13C NMR

An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

CVMD iMed, Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden
SP Process Development, Box 36, SE-151 21 Södertälje, Sweden
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00382………..http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00382
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A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

 

Paper

Abstract Image

Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7(AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease

Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit Departments of Medicinal Chemistry, Bioscience, §DMPK, Discovery Sciences Departments of Structure & Biophysics, Reagents and Assay Development, and #Screening Sciences and Sample Management, Astrazeneca, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00188
*(F.G.) Phone: +1-212-4780-822. E-mail: fabrizio.giordanetto@deshawresearch.com., *(D.P.) Phone: +46 31 7065 663. E-mail:daniel.pettersen@astrazeneca.com.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00188

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akenoic acid as a key step in the sysnthesis of AZD2716. Org. Proc. Res. Dev. 2016, 20(2),
262-269).

/////////atherosclerosis,  coronary artery disease,  fragment screening,  fragment-based drug discovery,   Secreted phospholipase A2,  sPLA2,  AZD2716, AZD-2716, AZD 2716, PRECLINICAL

c1c(cc(c(c1)C(=O)N)c2cccc(c2)CC(C(=O)O)C)Cc3ccccc3


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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 29 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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