ACHN-975 / Achaogen - LARVOL DELTA

Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014-2024). (PubMed, Front Microbiol) - "However, only ACHN-975 entered clinical phase I trials and was discontinued due to safety concerns, so far none of the LpxC inhibitors are available. This paper mainly focuses on the structure optimization, conformational relationship and animal toxicity of small molecule LpxC inhibitors over the past 10 years, especially in the last 5 years, in order to provide ideas for the development and clinical research of LpxC inhibitors."

Journal • Review • Infectious Disease

LpxC inhibition: Potential and opportunities with carbohydrate scaffolds. (PubMed, Carbohydr Res) - "This review briefly covers the advancement and progress made in LpxC inhibition. The field awaits the use of potential associated with carbohydrate-based scaffolds for LpxC inhibition and the discovery of anti-bacterial agents against Gram-negative infections."

Journal • Infectious Disease

The Complex Structure of Protein AaLpxC from Aquifex aeolicus with ACHN-975 Molecule Suggests an Inhibitory Mechanism at Atomic-Level against Gram-Negative Bacteria. (PubMed, Molecules) - "We employed isothermal titration calorimetry for the measurement of affinity between AaLpxC mutants and ACHN-975, and the results manifest the key residues (His74, Thr179, Tyr212, His226, Asp230 and His253) for interaction. The determined AaLpxC crystal structure in complex with ACHN-975 is expected to serve as a guidance and basis for the design and optimization of molecular structures of ACHN-975 analogues to develop novel drug candidates against Gram-negative bacteria."

Journal • Infectious Disease • Inflammation

[VIRTUAL] Synthesis of truncated, methanethiosulfonate-containing analogues of ACHN-975 (ASHP 2020) - "The inhibitory profile and pharmacokinetic properties of LpxC inhibitors can be improved through modifications to previously optimized clinical candidates. A careful evaluation of clinical trial outcomes for LpxC inhibitors provided the inspiration to redesign this putative drug candidate to address the significant limitations of solubility, route of administration and adverse effects."

-Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety. (PubMed, ChemMedChem) - "ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia...A phosphate prodrug of 26 was developed that provided solubility of >30 mg/mL for parenteral administration and conversion to the active drug with a T1/2 of approximately 2 minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development."

Clinical • Journal • Cardiovascular • Hypotension

Potent LpxC Inhibitors with In Vitro Activity Against Multi-Drug Resistant Pseudomonas aeruginosa. (PubMed, Antimicrob Agents Chemother) - "Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials. In addition, we describe the profile of three additional LpxC inhibitors that were identified as potential lead molecules. These efforts did not produce an additional development candidate with a sufficiently large therapeutic window and the program was subsequently terminated."

Journal • Preclinical