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New TB Drug Enters Trials Neglected Diseases: Milestone comes despite waning pharma interest

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TBA-354

New TB Drug Enters Trials

Neglected Diseases: Milestone comes despite waning pharma interest
chemical and eng news
Volume 93 Issue 8 | p. 5 | News of The Week
Issue Date: February 23, 2015 | Web Date: February 19, 2015

For the first time in six years, a new tuberculosis drug candidate has entered human clinical trials. Supported by the nonprofit Global Alliance for TB Drug Development, Phase I testing of TBA-354 began on Feb. 19.

TBA-354 is a nitroimidazole, a class of drugs effective against drug-resistant TB. The compound arose from a collaboration among the TB Alliance and researchers at New Zealand’s University of Auckland and the University of Illinois, Chicago, to find a next-generation nitroimidazole with more potent bactericidal activity and more favorable pharmacokinetic properties

TBA 354

CAS No: 1257426-19-9, 1403987-02-9

436.34, C19 H15 F3 N4 O5

2-Nitro-6(S)-[6-[4-(trifluoromethoxy)phenyl]pyridin-3-ylmethoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]

5H-​Imidazo[2,​1-​b]​[1,​3]​oxazine, 6,​7-​dihydro-​2-​nitro-​6-​[[6-​[4-​(trifluoromethoxy)​phenyl]​-​3-​pyridinyl]​methoxy]​-​, (6S)​-

6S)-2-Nitro-6-({6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

TBA-354 is a potent anti-tuberculosis compound; maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates.

TBA-354

Nitroimidazoles represent a promising new class of anti-tubercular agents with potential for the treatment of drug sensitive and drug resistant disease. Two first generation compounds (PA-824 and OPC67683) are currently in clinical development. To maximize the potential of this class for tuberculosis (TB), we conducted a medicinal chemistry program to identify a next generation nitroimidazole. Ultimately, we selected TBA-354 [(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine] for in-depth profiling and preclinical development.
TBA-354 is more potent than PA-824 against M. tuberculosis in vitro, and against acute and established murine TB. This potency advantage is maintained on dosing as monotherapy in the initial and continuation phases of treatment, and when administered in combination with moxifloxacin and pyrazinamide. TBA-354 possesses a favorable pharmacokinetic (PK) profile with good oral bioavailability and excellent exposures in preclinical species. Due to these combined advantages, predicted clinically therapeutic doses are once daily and low, differentiating TBA-354 as a next generation anti-tubercular nitroimidazole.

TBA-354 was discovered by the TB Alliance in partnership with the University of Auckland and the University of Illinois at Chicago. The TB Alliance is a not-for-profit product development partnership (PDP) that operates like a biopharmaceutical company. The medicinal chemistry that led to discovery of TBA-354 was conducted at the Auckland Society for Cancer Research Center at University of Auckland and the biology was conducted at the University of Illinois at Chicago. Further in-depth profiling of the compound was led by the TB Alliance in collaboration with Johns Hopkins University, University of Illinois at Chicago and RTI International. Financial support for this project was provided by the Bill & Melinda Gates Foundation and UK Aid. The work was presented at ICAAC 2012 in San Francisco on Sept 10th 2012.

TBA-354’s excellent efficacy and pharmacokinetic profile make it a promising candidate to deliver superior bactericidal results from a small daily pill. The evidence of TBA-354’s effectiveness was found in animal models of TB, which, while often predictive, have their limitations. Clinical trials are needed to evaluate TBA-354’s effectiveness against TB in patients. Before proceeding to clinical trials, the safety and tolerability of TBA-354 must be evaluated; these toxicology and safety pharmacology studies are underway and will provide more information concerning the potential of this compound.

One of the major challenges of TB treatment, as well as drivers of drug-resistance remains the length and complexity of current treatment. Defeating the TB pandemic will require new drugs that shorten and simplify treatment. Given the disproportionate skew of the TB burden in the developing world, all new TB treatments must also be inexpensive enough to facilitate scale-up. As the most potent anti-tubercular nitroimidazole under development to date, TBA-354 offers great promise in many ways. Its potency may enable the reduction of length, cost, and side-effects of TB treatment. It is compatible with commonly used AIDS medications in ways that some currently used TB treatments are not. Further, nitroimadzoles have already proven combinable with other experimental TB drugs to form novel treatments regimens with the potential to cure both drug-sensitive and MDR-TB.

TBA-354 belongs to the nitroimadazole class. Other drugs from this class have exhibited promising activity against TB bacteria in the lab and in clinical trials — two of the most advanced new TB drug candidates (PA-824and delamanid) belong to this class. Having shown greater potency compared to PA-824 and an improved pharmacokinetic profile compared to delamanid, along with other promising properties, TBA-354 offers the potential to shorten and simplify TB treatment further than therapies currently under clinical development. Its increased potency against TB could also reduce the cost, pill size, frequency and/or side effects of treatment with a nitroimidazole by achieving comparable efficacy with less drug amount. Importantly, because it belongs to a novel class of drugs, TBA-354 projects to be effective in treating both drug-sensitive and drug-resistant TB.

TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB

• It is the first new TB drug candidate to begin a Phase 1 clinical trial since 2009

• 1.5 million people die each year from TB, and more than nine million were diagnosed with the disease

FEB 2015 NEW YORK — The Global Alliance for TB Drug Development (TB Alliance) has commenced the first human trial of a new tuberculosis (TB) drug candidate, designated TBA-354, the not for profit organization announced Wednesday..

It is the first new TB drug candidate to begin a Phase 1 clinical trial since 2009.

The World Health Organization reported that 1.5 million people die each year from TB, and more than nine million were diagnosed with the disease. The lack of short, simple, and effective treatments is a significant obstacle to TB control.

Owing to lack of economic incentive to develop new tools, there are not enough promising drugs in the pipeline, which could hinder efforts to develop the appropriate treatments needed to combat the TB epidemic.

“There is a critical gap of new compounds for TB,” said Mel Spigelman, MD, President and CEO of TB Alliance.

“The advancement of TBA-354 into clinical testing is a major milestone, not only because of the potential it shows for improving TB treatment, but because it is the first new TB drug candidate to begin a Phase 1 clinical trial in six years.”

TBA-354 emerged from studies designed to identify a next generation nitroimidazole for TB. It comes from the nitroimidazole class of chemicals, known for being effective against drug-sensitive and drug-resistant tuberculosis.

The class also includes the experimental TB drug pretomanid (formerly PA-824), which is being tested as a component of other novel regimens in multiple clinical trials.

TB Alliance conducted the studies in collaboration with the University of Auckland and University of Illinois-Chicago. Once identified, TB Alliance further advanced TBA-354 through pre-clinical development and is now the sponsor of the Phase 1 study

“Our chemistry team has worked on this since 2006 when the TB Alliance approached us to help with this project,” said Professor Bill Denny, director of the Auckland Cancer Society Research Centre and a Principal Investigator of the Maurice Wilkins Centre at the University of Auckland. “We made several hundred compounds, from which TBA-354 was selected for clinical development in 2011.”

“It’s very pleasing for us to see this drug go all the way through to Phase one clinical trial. It’s a validation of our work designing this compound to create a new and improved drug for the treatment of tuberculosis,” stated Denny in a statement.

In preclinical studies, TBA-354 demonstrated more potent anti-bactericidal and sterilizing activity compared to pretomanid. Recruitment is under way to enroll nearly 50 U.S. volunteers for the randomized, double-blind Phase 1 trial, which will evaluate the safety, tolerability, pharmacokinetics, and dosing of TBA-354.

In late 2012 a promising New Zealand compound targeting treatment-resistant tuberculosis (TB) was selected as a drug candidate by international non-profit drug developer the Global Alliance for TB Drug Development (TB Alliance).

NZ TB drug selected

Image: Micrograph of Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Image courtesy of Dr Ray Butler and Janice Carr (Centres for Disease Control).

New drug candidate TBA-354 was designed by scientists from the Auckland Cancer Society Research Centre (ACSRC) and Maurice Wilkins Centre in partnership with the TB Alliance and University of Illinois at Chicago. The TB Alliance expects to complete preclinical studies by early 2013, and then seek permission from the US Food and Drug Administration to begin human trials.

TB is second only to HIV/AIDS as the greatest infectious killer worldwide. While most cases and deaths occur in low and middle income countries, it is a major health concern in the Asia-Pacific region. Treatment regimens are complex, lengthy and challenging to follow and the disease is developing resistance to current antibiotics. If a new drug proves more effective than current treatments it may reduce the duration, cost and side effects of treatment.

Laboratory studies to date have been very promising, with TBA-354 proving much more potent and broad-spectrum than PA-824, the first-generation compound it was designed to improve upon. TBA-354 and PA-824 are members of the first new class of drugs developed for TB in nearly fifty years and the first designed to attack the persistent form.

the TB Alliance contracted the New Zealand scientists to develop second-generation compounds to overcome some of its known limitations. The New Zealanders optimised each part of the drug, and in the process developed a new method of synthesis that will simplify and reduce the cost of producing drugs of this class.

“TBA-354 is an improved, second-generation version of PA-824,” says Professor Bill Denny,
ACSRC Co-Director and a Maurice Wilkins Centre principal investigator. “It is much more
potent than PA-824, longer lasting, and has greater activity against resistant strains. Recent
trials show that PA-824 can dramatically shorten the treatment period for TB, and it’s
encouraging that in TBA-354 we have a compound that is clearly superior to it.”

“This has been an excellent and productive international collaboration, across groups with
different skills, where we have learned much that we can apply in future,” says Associate
Professor Brian Palmer of the ACSRC and Maurice Wilkins Centre, who led the project’s
chemistry team of Drs Adrian Blaser, Iveta Kmentova, Hamish Sutherland and Andrew
Thompson.

“New Zealand has an outstanding reputation in drug discovery and it’s exciting to see the
ACSRC’s expertise in cancer drug development being applied to the fight against one of
the most devastating infectious diseases in the world,” says Centre Director Professor
Rod Dunbar.

 http://www.google.co.in/patents/EP2459571A1?cl=en

[0093] E. Synthesis of (6S)-2-nitro-6-({6-[4-(trifluoromethoxy)phenyI]-3- pyridinyI}methoxy)-6,7-dihydro-5H-imidazo[2,l-A][l53]oxazine (6) by the method of Scheme 4.

Figure imgf000025_0001

NaH (60% w/w, 0.584 g, 14.6 mmol) was added to a solution of oxazine alcohol 41 (2.073 g, 1 1.2 mmol) and 2-chloro-5-(chloromethyl)pyridine (48) (2.0 g, 12.3 mmol) in anhydrous DMF (40 mL) at 5 0C. The resulting mixture was stirred at room temperature for 16 h and then quenched with water (150 mL). The precipitate was filtered off, washed with water and dried to give (65)-6-[(6-chloro-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5//-imidazo[2,l- ft][l,3]oxazine (49) (3.39 g, 97%) as a light yellow solid: mp 191-193 0C; 1H NMR [(CD3)2SO] δ 8.37 (d, J- 2.3 Hz, 1 H), 8.02 (s, 1 H), 7.79 (dd, J = 8.3, 2.4 Hz, 1 H), 7.51 (br d, J = 8.2 Hz, 1 H), 4.74 (d, J= 12.4 Hz, 1 H), 4.69-4.64 (m, 2 H), 4.47 (d, J= 1 1.8 Hz, 1 H), 4.29-4.21 (m, 3 H). HRESIMS calcd for C12Hi2ClN4O4 mlz [M + H]+ 313.0513, 311.0542, found 313.0518, 311.0545.

Chloride 49 (1.0 g, 3.22 mmol) and 4-(trifluoromethoxy)phenylboronic acid (44) (0.788 g, 3.82 mmol) were suspended in DME (50 mL) and an aqueous solution Of K2CO3 (2M, 10 mL) was added. The mixture was purged with N2 and then treated with Pd(dppf)Cl2 (50 mg, 0.068 mmol) and stirred at 85 0C in an N2 atmosphere for 1 day, monitoring by MS. Further 44 (0.150 g, 0.728 mmol) was added and the mixture was stirred at 85 0C in an N2 atmosphere for 1 day. The resulting mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 100 mL). The dried (MgSO4) organic layers were adsorbed onto silica gel and chromatographed on silica gel, eluting with EtOAc. Trituration of the product in Et2O gave 6 (0.942 g, 67%) as a white powder: mp 217-219 0C; 1H NMR [(CD3)2SO] δ 8.63 (d, J = 1.7 Hz, 1 H), 8.20 (dt, J = 8.9, 2.1 Hz, 2 H), 8.03 (s, 1 H), 7.99 (dd, J = 8.2, 0.5 Hz, 1 H), 7.84 (dd, J = 8.2, 2.2 Hz, 1 H), 7.47 (dd, J = 8.8, 0.8 Hz, 2 H), 4.77 (d, J = 12.3 Hz, 1 H), 4.71-4.68 (m, 2 H), 4.49 (d, J= 11.7 Hz, 1 H), 4.31-4.26 (m, 3 H). Anal. (Ci9Hi5F3N4O5) C, H, N. HPLC purity: 98.9%.

…………………

PATENT

http://www.google.com/patents/US20120028973

 

…………………

PAPER

Journal of Medicinal Chemistry (2010), 53(23), 8421-8439

http://pubs.acs.org/doi/full/10.1021/jm101288t

217 – 219 °C MP

http://pubs.acs.org/doi/suppl/10.1021/jm101288t/suppl_file/jm101288t_si_001.pdf

(6S)-2-Nitro-6-({6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (93).
1)via bromide 160 :
Reaction of bromide160and 4-(trifluoromethoxy)phenylboronic acidunder the Suzuki coupling conditions described in Procedure A, followed by chromatographyof the product on silica gel, eluting with EtOAc, gave93(70%) as a cream solid: mp 217-219°C;
1H NMR [(CD3)2SO]
δ8.63 (d,J =1.7 Hz, 1 H),
8.20 (dt,J =8.9, 2.5 Hz, 2 H),
8.03 (s,1 H),
7.99 (dd,J =8.2, 0.5 Hz, 1 H),
7.84 (dd,J =8.2, 2.2 Hz, 1 H),
7.47 (br d,J =8.8 Hz, 2H),
4.77 (d,J =12.3 Hz, 1 H),
4.74-4.67 (m, 2 H),
4.49 (br d,J =11.7 Hz, 1 H),
4.33-4.22(m, 3 H).
Anal. (C19H15F3N4O5) C, H, N.F

 

Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
§ Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States
J. Med. Chem., 2010, 53 (23), pp 8421–8439
DOI: 10.1021/jm101288t

Andrew M. Thompson

*Corresponding author. Phone: (+649) 923 6145. Fax: (+649) 373 7502. E-mail: am.thompson@auckland.ac.nz.

+64 9 373 7599

Map of University of Auckland-Grafton Campus 85 Park Rd, Grafton, Auckland 1023, New Zealand
Street View
University of Auckland-Grafton Campus 85 Park Rd Grafton, Auckland 1023, New Zealand

Address details

M&HS BUILDING 504

Level 1, Room 504-117

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Auckland 1023

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REF

International Journal of Computational Biology and Drug Design (2014), 7(1), 1-30.

http://www.inderscience.com/info/inarticle.php?artid=58583

 

 

University of Auckland – Faculty of Medical & Health Science

 

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2 Comments

  1. Ignacio de Alfonso says:

    The sctructure depicted are not steroequivalents… Different enantioners drawn along the text. On the other hand, really interesting!

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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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