Objective & Challenges: Objective was to identify an optimized anti-bacterial lead molecule with in vivo efficacy in relevant infection models an acceptable safety profile, and a patentable series.
Challenge was to develop a more efficacious compound than the reference standard.
Study design: Compounds were designed and synthesized with variation. 232 compounds were generated from 8 different series. 3 molecules were identified from different series meeting the early lead criteria & 148 compounds were generated from 3 series. 2 patentable leads were identified from structurally diverse series out which AU-XXX was nominated as candidate molecule.
Outcome: Improved potency (1-4x) with expanded spectrum of activity was observed. In vitro to in vivo translation. Favourable DMPK properties - Metabolically stable (MLM, RLM, PHLM) with good solubility and low serum protein binding. No CYP liability. Probe toxicity studies indicate better safety profile than the reference compound.
Results: AU-XXX exhibited Minimum Inhibitory Concentration (MIC) of 1-2 μg/mL against different phenotypes of Gram-positive pathogens S. aureus, E. faecalis and E. faecium. AU-XXX exhibited good in vitro antibacterial activity against respiratory pathogens S. pneumoniae, H. influenzae, and M. cattarrhalis. AU-XXX exhibited good in vitro antibacterial activity against respiratory pathogens S. pneumoniae, H. influenzae, and M. cattarrhalis. AU-XXX was evaluated in murine systemic and lung infection models and it demonstrated in vivo efficacy better than comparator reference drug. Absorption, distribution, metabolism and excretion (ADME) of AU-XXX in mouse, rat and dog was favourable in support of preclinical safety studies and clinical development. Toxicity studies were conducted in rats with dosage 200 mg/kg/day for 14 days. The incidence and severity observed was less compared to the reference compound.
Microbiology capabilities: Anti-infective research and development is a core research facility. Key resources are fully dedicated to enable multiple anti-infectives research programs to be conducted to proof of concept. Ability to reproduce and setup in-house assays rapidly. Best/first in class medicinal chemistry expertise. Full toxicology back-up to achieve IND optimally.
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