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VNRX-5133 from VENATORX PHARMACEUTICALS

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VNRX-5133
CAS: 1613268-23-7
Chemical Formula: C19H28BN3O5
Molecular Weight: 389.26
3-(2-((1r,4r)-4-((2-aminoethyl)amino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
 ( R)-3-( 2-( trans-4-( 2-aminoethylamino)cvclohexyl)acetamido)-2-hvdroxy-3-,4-dihydro-2H-benzo[el [l,21oxaborinine-8-carboxylic acid
Image result for VNRX-5133
  • Originator VenatoRx Pharmaceuticals
  • Developer  National Institute of Allergy and Infectious Diseases; VenatoRx Pharmaceuticals
  • Class Antibacterials; Cephalosporins; Small molecules
  • Mechanism of Action Beta lactamase inhibitors; Cell wall inhibitors

Highest Development Phases

  • Phase I Bacterial infections

Most Recent Events

  • 19 Mar 2018 VenatoRx Pharmaceuticals plans phase III pivotal trials in mid-2018
  • 03 Jan 2018 VNRX 5133 receives Fast Track designation for Bacterial infections (complicated urinary tract infections and complicated intra-abdominal infections) [IV-infusion] in USA
  • 03 Jan 2018 VNRX 5133 receives Qualified Infectious Disease Product status for Intra-abdominal infections in USA
  • clip
  • https://cen.acs.org/articles/96/web/2018/03/Drug-structures-made-public-New-Orleans.html

str4Credit: Tien Nguyen/C&EN

Presented by: Christopher J. Burns, president and chief executive officer of VenatoRx Pharmaceuticals

Target: β-lactamase enzymes, enzymes that inactivate β-lactam-based antibiotics enabling bacteria to resist their attacks

Disease: Gram-negative bacterial infections

Reporter’s notes: Another story with humble beginnings, this time with Burns and two colleagues sitting in a Panera Bread, with an idea. They wanted to offer a new compound in the class of β-lactam antibiotics, drugs which are “well-liked” by doctors, Burns said, and make up 60% of all antibiotic prescriptions. However, bacteria have developed defenses against these compounds in the form of β-lactamases, or as Burns dubbed them, “PAC-men.” These enzymes can chew up 1000 β-lactams per second, he said. VNRX-5133 was active against both serine-β-lactamases and metallo-β-lactamases in enzyme assays. It is being developed in combination with the antibiotic cefepime. VNRX-5133 fends off the PAC-men’s attacks, allowing cefepime to combat infection. The compound has gone through Phase I clinical trials and will be skipping ahead to Phase III later this year.

PATENT

WO 2014089365

Applicants: VENATORX PHARMACEUTICALS, INC [US/US]; 30 Spring Mill Drive Malvern, PA 19355 (US)
Inventors: BURNS, Christopher, J.; (US).
DAIGLE, Denis; (US).
LIU, Bin; (US).
MCGARRY, Daniel; (US).
PEVEAR, Daniel C.; (US).
TROUT, Robert E. Lee; (US)

https://patents.google.com/patent/WO2014089365A1/en

Christopher J. Burns, Ph.D.
President and Chief Executive Officer

Dr. Burns is Co-Founder, President and Chief Executive Officer of VenatoRx. He brings over 25 years of corporate and R&D experience within both major (RPR/Aventis) and specialty (ViroPharma, Protez…https://www.venatorx.com/leadership/

Antibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins,

cephalosporins, and carbapenems) are widely used because they have a strong bactericidal effect and low toxicity.

[0004] To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as “serine” or “metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community.

EXAMPLE 15 : ( R)-3-( 2-( trans-4-( 2-aminoethylamino)cvclohexyl)acetamido)-2-hvdroxy-3-,4-dihydro-2H-benzo[el [l,21oxaborinine-8-carboxylic acid

Step 1 : Synthesis of (R)-3-(2-(trans-4-(2-(tert-butoxycarbonylamino)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e] [ 1 ,2]oxaborinine-8-carboxylic acid.

[00240] To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (Example 6, 15 mg) in MeOH (2 mL) was added tert-butyl 2-oxoethylcarbamate (20 mg). Pd/C (10% by weight, 10 mg) was added and the reaction mixture was stirred under ¾ balloon overnight. The reaction mixture was filtrated and the solvent was then removed under reduced pressure and the residue was carried on to the next step without further purification. ESI-MS m/z 490.1 (MH)+.

Step 2: Synthesis of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid.

[00241] To (R)-3-(2-(trans-4-(2-(tert-butoxycarbonylamino)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (20 mg) in a flask was added 1 mL 4N HC1 in dioxane. The resulting reaction mixture was stirred at RT for 2hr. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 390 (MH)+.

Step 2: (R)-3-(2-(trans-4-((2-aminoethylamino)methyl)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e] [ 1 ,2]oxaborinine-8-carboxylic acid

[00229] Prepared from 3-[2-(2-{4-[(2-tert-Butoxycarbonylamino-ethylamino)-methyl]-cyclohexyl}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BC13 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 404 (MH)+.

/////////////////////////////VNRX-5133; VNRX5133; VNRX 5133, phase 1, VenatoRx Pharmaceuticals, BACTERIAL INFECTIONS, Christopher J. Burns

 NCCN[C@@H]1CC[C@@H](CC(NC2B(O)OC(C(C(O)=O)=CC=C3)=C3C2)=O)CC1

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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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