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IntelliSyn specializes in challenging synthetic targets and in cases where there are critical intellectual property security concerns. We have an expert knowledge base of recent synthetic developments and reliable, published sequences. We extensively survey the literature around the scaffold and then innovate to develop reliable and reproducible synthetic routes or optimize routes, in terms of yield, cost, or convergence. We perform a full range of chemistries, including multi-step asymmetric synthesis, heterocyclic chemistry, peptide chemistry, anhydrous/air-sensitive chemistry, and parallel synthesis. All compounds are purified by HPLC, CombiFlash, or SFC and characterized by proton and carbon NMR, mass spectrometry, and heavy metal content, according to project requirements. IntelliSyn provides a certificate of analysis and “publication-ready” experimental write-ups.

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Hit Identification.  Projects with quality starting points make faster progress and have lower attrition rates.  Identifying a quality lead is the project’s first committed step. To find leads, we employ whichever methods are most appropriate for each individual target, such as HTS, fragments, computational screening, and structure based design.  Selection of inferior starting points (typically due to the allure of high initial potency) generally leads to failure at later (much more expensive) stages for reasons that should have been predicted.

Citations:  Albert, JS; Fragment-based Lead Discovery in “Modern Approaches to Lead Discovery” Wiley Publications, 2010, 105 (Link)

Lead Optimization.  Compound synthesis is typically the most costly part of preclinical discovery efforts.  Despite this, many groups persist in focusing on “numbers of compounds” rather than “quality of compounds”.  These results in the wasted effort of making compounds that should have been predicted as not being viable as drugs due to, for example, poor physicochemical characteristics, metabolic risk factors, and presence of toxicophores.  We strive to use synthesis resources most effectively by ensuring quality design in each candidate through systematic target knowledge, mechanistic understanding, and predictive methodologies.

Our multi-disciplinary team has a demonstrated track record of optimizing against multiple parameters including these:

  • Target potency
  • Selectivity
  • Mechanism of Action
  • Permeability and efflux
  • Exposure and free fraction at the site of action
  • Physical properties consistent with high druggability
  • Metabolic rate, disposition, and  reactive metabolite risk profile
  • Mutagenicity
  • Off-target activity, including hERG and CYP P450s
[/vc_column_text][dt_gap height=”40″][/vc_column][/vc_row][vc_row anchor=”fragment” margin_top=”0″ margin_bottom=”0″ padding_left=”40″ padding_right=”40″ bg_position=”top” bg_repeat=”no-repeat” bg_cover=”false” bg_attachment=”false” padding_top=”40″ padding_bottom=”40″ parallax_speed=”0.1″][vc_column width=”1/1″][dt_fancy_title title=”Fragment based drug discovery” title_align=”center” title_size=”h3″ title_color=”default” title_bg=”disabled” separator_color=”default”][dt_gap height=”25″][vc_column_text]Our team members have been successfully employing FBDD for over a decade.  We have advanced numerous targets from fragments hits (micromolar affinity) through final optimization (nanomolar activity). We do this through focus on:

  • Identifying the most appropriate screening and hit validation assays
  • Identifying the right set of high quality fragments to screen
  • Selecting the best initial hits to advance
  • Efficiently progressing the hits while retaining low lipophilicity, high ligand efficiency and high druggability

Fragment-hit

References

  • Albert, JS; Edwards, PD; Identification of high-affinity beta-secretase inhibitors using fragment-based lead generation.  Fragment-Based Drug Discovery, 2008, Wiley (Link)
  • Albert, JS; Blomberg, N; et al. An integrated approach to fragment-based lead generation: philosophy, strategy and case studies from AstraZeneca’ Curr. Top. Med. Chem. 2007, 7, 1600 (Link)
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Every area of drug discovery has challenges, and this is especially true for compounds that act in the brain.  Our group has special expertise in discovering CNS drugs. We have a proven track record in multi-parameter optimization for CNS and drive SAR with the right in vitro and in vivo parameters. We design compounds with the appropriate physicochemical and topological characteristics to minimize efflux and metabolism, to enhance passive permeability and solubility, and to ultimately achieve the desired unbound drug in brain concentration.

References

Targets and Emerging Therapies for Schizophrenia, 2012, Wiley Press. Edited by Jeffrey S. Albert and Michael W. Wood (Link)

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