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AB 680

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MFYLCAMJNGIULC-KCVUFLITSA-N.png

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20190404lnp1-ab680.jpg

AB 680

C20H24ClFN4O9P2, 580.827 g/mol

Cas 2105904-82-1

1H-Pyrazolo[3,4-b]pyridin-4-amine, 6-chloro-N-[(1S)-1-(2-fluorophenyl)ethyl]-1-[5-O-[hydroxy(phosphonomethyl)phosphinyl]-β-D-ribofuranosyl]-

[[(2R,3S,4R,5R)-5-[6-chloro-4-[[(1S)-1-(2-fluorophenyl)ethyl]amino]pyrazolo[3,4-b]pyridin-1-yl]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]methylphosphonic acid

[({[(2R,3S,4R,5R)-5-(6-chloro-4-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic Acid

  • Originator C
  • Class Antineoplastics; Small molecules
  • Mechanism of Action 5-nucleotidase inhibitors; Adenosine A2 receptor antagonists
  • Phase I Cancer
  • 19 Nov 2018 Arcus Biosciences plans to initiate a clinical trial in Cancer in first half of 2019
  • 16 Oct 2018 Phase-I clinical trials in Cancer (In volunteers) in Australia (IV) (NCT03677973)
  • 30 Sep 2018 Preclinical pharmacodynamics data in Cancer presented at 4th CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CRI-CIMT-EATI-AACR – 2018)

Clip

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Credit: Tien Nguyen/C&EN

Presenter: Kenneth V. Lawson, senior scientist at Arcus Biosciences

Target: Ecto-5’-nucleotidase (CD73)

Disease: Cancer

Reporter’s notes: In the first talk of the day, Lawson introduced the idea of cancer drugs that target the host’s immune system. “Checkpoint inhibitors changed the way we think of treating cancer,” he said. These drugs successfully disrupt the binding interaction between a protein and a checkpoint protein that stops immune T cells from killing cancer cells. As a result, these drugs turn immune cells loose to attack tumor cells. But the drugs work only in about 30-40% of patients—an issue pharmaceutical companies like Arcus hope to address with new immunotherapies that can be taken in combination with checkpoint inhibitors.

Lawson’s team set out to inhibit an enzyme commonly found in tumors called CD73, the second of two enzymes which break down extracellular adenosine trisphosphate (ATP) to adenosine. Adenosine then binds to immunosuppressive receptors on immune cells and shuts them down. Yet developing a small molecule inhibitor of CD73 proved challenging, Lawson said. After striking out with high-throughput screening, the team turned to CD73’s natural substrate for inspiration. However, the molecule possessed more than one phosphate group, which is notoriously a liability for drug molecules because small molecules with such negative changes struggle to cross cell membranes. The team’s goal was to remove the phosphate groups, Lawson says, but things didn’t exactly go according to plan. After showing the audience a series of compounds from structure-activity relationship (SAR) studies—slides no medicinal chemistry talk would be complete without—Lawson revealed the structure of their final clinical compound AB680 as the sound of people flipping notebook sheets rippled across the room. Synthesized in 34% overall yield, the candidate ultimately included two phosphate groups—a feature that surprised audience members.

Tests revealed that AB680 can be given intravenously but the compound also showed moderate oral bioavailability. Lawson suggested a possible route for how the molecule might pass from the digestive tract to the bloodstream, a paracellular mechanism by which molecules cross the epithelium by passing through the space between cells. AB680 showed “extraordinary potency,” inhibiting CD73 in human T-cells at a concentration of 0.008 nM. The compound has a 4 day half-life, which means it could be dosed every two weeks, coinciding with the dosing schedule for patients who receive a checkpoint inhibitor. AB680 is currently in Phase 1 clinical trials with healthy patients.

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PATENT

US2017267710

https://patentscope.wipo.int/search/en/detail.jsf?docId=US204141996&tab=PCTDESCRIPTION&maxRec=1000

Purinergic signaling, a type of extracellular signaling mediated by purine nucleotides and nucleosides such as ATP and adenosine, involves the activation of purinergic receptors in the cell and/or in nearby cells, resulting in the regulation of cellular functions. Most cells have the ability to release nucleotides, which generally occurs via regulated exocytosis (see Praetorius, H. A.; Leipziger, J. (1 Mar. 2010) Ann Rev Physiology 72(1): 377-393). The released nucleotides can then be hydrolyzed extracellularly by a variety of cellular membrane-bound enzymes referred to as ectonucleotidases.
      Ectonucleotides catalyze the conversion of ATP to adenosine, an endogenous modulator that impacts multiple systems, including the immune system, the cardiovascular system, the central nervous system, and the respiratory system. Adenosine also promotes fibrosis in a variety of tissues. In the first step of the production of adenosine, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also known as CD39 (Cluster of Differentiation 39), hydrolyzes ATP to ADP, and then ADP to AMP. In the next step, AMP is converted to adenosine by 5′-nucleotidase, ecto (NT5E or 5NT), also known as CD73 (Cluster of Differentiation 73).
      The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to various cells (e.g., immune cells). Alteration of these enzymatic activities can change the course or dictate the outcome of several pathophysiological events, including cancer, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury, suggesting that these ecto-enzymes represent novel therapeutic targets for managing a variety of disorders.
      CD73 inhibition with monoclonal antibodies, siRNA, or small molecules delays tumor growth and metastasis (Stagg, J. (2010) PNAS U.S.A. 107:1547-52). For example, anti-CD73 antibody therapy was shown to inhibit breast tumor growth and metastasis in animal models (Stagg, J. (26 Jan. 2010) PNAS U.S.A, 107(4):1547-52). In addition, the use of antibodies that specifically bind CD73 has been evaluated for the treatment of bleeding disorders (e.g., hemophilia) (U.S. Pat. No. 9,090,697). Recently, there have been several efforts to develop therapeutically useful CD73 small molecule inhibitors. For example, Bhattarai et al. ((2015) J Med Chem 58:6248-63) have studied derivatives and analogs of α,β-Methylene-ADP (AOPCP), one of the most metabolically stable, potent and selective CD73 inhibitors known, and purine CD73 derivatives have been reported in the patent literature (WO 2015/164573). However, the development of small molecules has been hampered due to, for example, less than ideal metabolic stability.
      In view of the role played by CD73 in cancer, as well as a diverse array of other diseases, disorders and conditions, and the current lack of CD73 inhibitors available to medical practitioners, new CD73 inhibitors, and compositions and methods associated therewith, are needed.

Example 92

Synthesis of [({[(2R,3S,4R,5R)-5-(6-chloro-4-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)methyl]phosphonic Acid


      The title compound was synthesized in similar fashion to Example 87. 1H NMR (400 MHz, DMSO-d 6) δ 9.28-9.15 (m, 1H), 8.33 (dd, J=1.5, 0.7 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.29 (dd, J=7.8, 5.6 Hz, 1H), 7.23-7.08 (m, 2H), 6.00 (d, J=4.2 Hz, 1H), 5.65-5.51 (m, 1H), 4.48 (t, J=4.9 Hz, 1H), 4.26 (t, J=4.5 Hz, 1H), 4.05 (dq, J=10.1, 5.9, 5.2 Hz, 2H), 3.88 (dt, J=11.3, 6.0 Hz, 1H), 2.29-2.08 (t, J=20.4 Hz, 2H), 1.53 (d, J=6.8 Hz, 3H). ESI MS [M+H] + for C 19H24ClFN 592, calcd 582.1. found 582.1.

PATENT

WO 2017120508

////////////////ARCUS, AB 680, AB680, AB-680, PHASE 1

https://www.arcusbio.com/wp-content/uploads/2018/04/AACR_AB680_1756_final_90x42-abstract-4886.pdf

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Fc1ccccc1[C@H](C)Nc4cc(Cl)nc3c4cnn3[C@@H]2O[C@H](COP(=O)(O)CP(=O)(O)O)[C@@H](O)[C@H]2O

CC(C1=CC=CC=C1F)NC2=CC(=NC3=C2C=NN3C4C(C(C(O4)COP(=O)(CP(=O)(O)O)O)O)O)Cl

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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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