Lisofylline analogs and methods for use
Patent Number: US8987321B2 (related patents, US8871764B2 and US9278098B2, are also available)
Executive Summary:
General Description: The present invention provides analogs of LSF, and synthetic methods for the preparation of such analogs. The analogs can have greater potency and oral bioavailability than LSF. The analogs have the active side chain moiety (5-R-hydroxyhexyl) of LSF. The invention also includes derivatives of LSF. The disclosed analogs can be substituted with a variety of nitrogen-contained heterocyclic compounds or on the hydroxyl group of the side chain. Accordingly, the invention provides 1-substituted 5-hexanol compounds having additional substitution on the hydroxyl group. The synthetic methods are essential for the potency and bioavailability of LSF analogs.
Scientific Progress: Validation of the ability of LSF analogs to stimulate insulin release and their protective effects in mouse islet cells
Future Directions:
Strengths:
Patent Status:
Publication PMID: 16650991, 8951223, 10090779
Publications:
Inventor Bio: Timothy L. MacDonald
http://chemistry.as.virginia.edu/people/profile/tlm
Executive Summary:
- Invention Type: Therapeutics
- Patent Status: US Grant
- Patent Link: https://patents.google.com/patent/US8987321B2/
- Research Institute: University of Virginia
- Disease Focus: Inflammatory and Autoimmune Diseases, Diabetes
- Basis of Invention: Methods for synthesizing lisofylline (LSF) analogs, which contain the active side chain moiety (5-R-hydroxyhexyl) and a variety of nitrogen-contained heterocyclic compounds or on the hydroxyl group of the side chain
- How it works: Small molecules based on the LSF backbone using the method described can have enhanced potency, selectivity, and oral bioavailability in treating type 1 diabetes and other inflammatory diseases
- Lead Challenge Inventor: Timothy L. MacDonald
- Inventors: Timothy L. MacDonald, Jerry L. Nadler, Peng Cui
- Development Stage: Pre-clinical
- Novelty:
- Synthetic methods for the preparation of LSF analogs
- Clinical Applications:
- Diabetes treatment
General Description: The present invention provides analogs of LSF, and synthetic methods for the preparation of such analogs. The analogs can have greater potency and oral bioavailability than LSF. The analogs have the active side chain moiety (5-R-hydroxyhexyl) of LSF. The invention also includes derivatives of LSF. The disclosed analogs can be substituted with a variety of nitrogen-contained heterocyclic compounds or on the hydroxyl group of the side chain. Accordingly, the invention provides 1-substituted 5-hexanol compounds having additional substitution on the hydroxyl group. The synthetic methods are essential for the potency and bioavailability of LSF analogs.
Scientific Progress: Validation of the ability of LSF analogs to stimulate insulin release and their protective effects in mouse islet cells
Future Directions:
- Validation in animal models and in clinical trials
Strengths:
- The LSF analogs may have greater potency and oral bioavailability for treating type 1 diabetes
Patent Status:
- Priority date: 2005-08-29
- Filing date: 2014-01-16
- Publication date: 2015-03-24
- Grant date: 2015-03-24
Publication PMID: 16650991, 8951223, 10090779
Publications:
- Cui P, Macdonald TL, Chen M, Nadler JL., Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes (2006). Bioorg Med Chem Lett. 2006 Jul 1;16(13):3401-5. Epub 2006 May 2.
- Thompson CD, Kinter MT, Macdonald TL. Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate (1996). Chem Res Toxicol. 1996 Dec;9(8):1225-9.
- Hopper DW, Ragan SP, Hooks SB, Lynch KR, Macdonald TL (1999). Structure--activity relationships of lysophosphatidic acid: conformationally restricted backbone mimetics. J Med Chem. 1999 Mar 25;42(6):963-70.
Inventor Bio: Timothy L. MacDonald
http://chemistry.as.virginia.edu/people/profile/tlm