Benzocycloheptyl analogs having sphingosine 1-phosphate receptor activity
Patent Number: US7915315B2
 
Executive Summary:
  • Invention Type: Therapeutic
  • Patent Status: US grant, Active
  • Patent Link: https://patents.google.com/patent/US7915315B2/
  • Research Institute: University of Virginia
  • Disease Focus: Inflammatory and Autoimmune Diseases, Diabetes
  • Basis of Invention: Novel, potent, and selective agents that are agonists of the S1P receptor
  • How it works: The compounds are sphingosine analogs which, after phosphorylation, can behave as agonists at S1P receptors
  • Lead Challenge Inventor: Kevin R. Lynch
  • Inventors: Kevin R. Lynch, Timothy L. MacDonald
  • Development Stage: In vivo & in vitro activity
  • Novelty:
    • Easy synthesis of new analogues
    • Enhanced potency, selectivity, and oral bioavailability
  • Clinical Applications:
    •  Diabetes
    • Transplantation
    • Autoimmune diseases
    • Neuropathic pain 
 
General Description: Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family. S1P receptors make good drug targets because individual receptors are both tissue and response specific. The present invention provides compounds that have agonist activity at one or more of the S1P receptors.
 
Future Directions:
  • Animal trials for preclinical validation
 
Strengths:
  • Family compounds with strong affinity and high selectivity for S1P receptor subtypes
 
Weaknesses:
  • Previous S1P agonist already in clinical trials
 
Patent Status:
  • Priority date: 2006-11-21
  • Filing date: 2009-10-08
  • Publication date: 2011-03-29
  • Grant date: 2011-03-29
 
Publications:
  • Bajwa A, Rosin DL, Chroscicki P, Lee S, Dondeti K, Ye H, Kinsey GR, Stevens BK, Jobin K, Kenwood BM, Hoehn KL, Lynch KR, Okusa MD, Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury., 2014; Journal of the American Society of Nephrology : JASN. PMID: 25145931.
  • Kharel Y, Raje M, Gao M, Gellett AM, Tomsig JL, Lynch KR, Santos WL, Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate., 2012; The Biochemical journal. 447(1) 149-57. PMID: 22747486| PMCID: PMC3443596
  • Lynch KR, Building a better sphingosine kinase-1 inhibitor., 2012; The Biochemical journal. 444(1) e1-2. PMID: 22533672
  • Knott K, Kharel Y, Raje MR, Lynch KR, Santos WL, Effect of alkyl chain length on sphingosine kinase 2 selectivity., 2012; Bioorganic & medicinal chemistry letters. 22(22) 6817-20. PMID: 22321213 | PMCID: PMC3394931
  • Kharel Y, Mathews TP, Gellett AM, Tomsig JL, Kennedy PC, Moyer ML, Macdonald TL, Lynch KR, Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate., 2011; The Biochemical journal. 440(3) 345-53. PMID: 21848514 | PMCID: PMC3443603
  • East JE, Carter KM, Kennedy PC, Schulte NA, Toews ML, Lynch KR, Macdonald TL, Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist., 2011; MedChemComm. 2(4) 325-330. PMID: 22180836 | PMCID: PMC3237054
  • Kennedy PC, Zhu R, Huang T, Tomsig JL, Mathews TP, David M, Peyruchaud O, Macdonald TL, Lynch KR, Characterization of a sphingosine 1-phosphate receptor antagonist prodrug., 2011; The Journal of pharmacology and experimental therapeutics. 338(3) 879-89. PMID: 21632869 | PMCID: PMC3164350
  • Raje MR, Knott K, Kharel Y, Bissel P, Lynch KR, Santos WL, Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors., 2011; Bioorganic & medicinal chemistry. 20(1) 183-94. PMID: 22137932 | PMCID: NIHMS338841
  • Kennedy AJ, Mathews TP, Kharel Y, Field SD, Moyer ML, East JE, Houck JD, Lynch KR, Macdonald TL, Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells., 2011; Journal of medicinal chemistry. 54(10) 3524-48. PMID: 21495716 | PMCID: PMC3119570
  • Awad AS, Rouse MD, Khutsishvili K, Huang L, Bolton WK, Lynch KR, Okusa MD, Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes., 2011; Kidney international. 79(10) 1090-8. PMID: 21289599 | PMCID: PMC3155206
  • Kharel Y, Mathews TP, Kennedy AJ, Houck JD, Macdonald TL, Lynch KR, A rapid assay for assessment of sphingosine kinase inhibitors and substrates., 2011; Analytical biochemistry. 411(2) 230-5. PMID: 21216217 | PMCID: PMC3049835
  • Mathews TP, Kennedy AJ, Kharel Y, Kennedy PC, Nicoara O, Sunkara M, Morris AJ, Wamhoff BR, Lynch KR, Macdonald TL, Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors., 2010; Journal of medicinal chemistry. 53(7) 2766-78. PMID: 20205392 | PMCID: PMC2875079
  • Bajwa A, Jo SK, Ye H, Huang L, Dondeti KR, Rosin DL, Haase VH, Macdonald TL, Lynch KR, Okusa MD, Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury., 2010; Journal of the American Society of Nephrology : JASN. 21(6) 955-65. PMID: 20338995 | PMCID: PMC2900956
  • East JE, Kennedy AJ, Tomsig JL, De Leon AR, Lynch KR, Macdonald TL, Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX)., 2010; Bioorganic & medicinal chemistry letters. 20(23) 7132-6. PMID: 20951039 | PMCID: PMC2975792
  • Petrie Aronin CE, Sefcik LS, Tholpady SS, Tholpady A, Sadik KW, Macdonald TL, Peirce SM, Wamhoff BR, Lynch KR, Ogle RC, Botchwey EA, FTY720 promotes local microvascular network formation and regeneration of cranial bone defects., 2009; Tissue engineering. Part A. 16(6) 1801-9. PMID: 20038198 | PMCID: PMC2949231
  • Tomsig JL, Snyder AH, Berdyshev EV, Skobeleva A, Mataya C, Natarajan V, Brindley DN, Lynch KR, Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo., 2009; The Biochemical journal. 419(3) 611-8. PMID: 19215222 | PMCID: PMC2677185
  • Foss FW, Mathews TP, Kharel Y, Kennedy PC, Snyder AH, Davis MD, Lynch KR, Macdonald TL, Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs., 2009; Bioorganic & medicinal chemistry. 17(16) 6123-36. PMID: 19632123 | PMCID: PMC2793099
  • Okusa MD, Lynch KR, Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury., 2009; Drug discovery today. Disease mechanisms. 4(1) 55-59. PMID: 19448841 | PMCID: PMC2682423
  • Lynch KR, Macdonald TL, Sphingosine 1-phosphate chemical biology., 2008; Biochimica et biophysica acta. 1781(9) 508-12. PMID: 18638568 | PMCID: PMC3412363
  • Jo SK, Bajwa A, Ye H, Vergis AL, Awad AS, Kharel Y, Lynch KR, Okusa MD, Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury., 2008; Kidney international. 75(2) 167-75. PMID: 18971925 | PMCID: PMC2646633
  • Wamhoff BR, Lynch KR, Macdonald TL, Owens GK, Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype., 2008; Arteriosclerosis, thrombosis, and vascular biology. 28(8) 1454-61. PMID: 18535287 | PMCID: PMC2605659
  • Hughes JE, Srinivasan S, Lynch KR, Proia RL, Ferdek P, Hedrick CC, Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages., 2008; Circulation research. 102(8) 950-8. PMID: 18323526 | PMCID: PMC2875063
  • Rivera-Lopez CM, Tucker AL, Lynch KR, Lysophosphatidic acid (LPA) and angiogenesis., 2008; Angiogenesis. 11(3) 301-10. PMID: 18504643 | PMCID: PMC2677190
  • Jo SK, Bajwa A, Awad AS, Lynch KR, Okusa MD, Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease., 2008; Kidney international. 73(11) 1220-30. PMID: 18322542 | PMCID: PMC2614447
  • Cui P, McCalmont WF, Tomsig JL, Lynch KR, Macdonald TL, alpha- and beta-substituted phosphonate analogs of LPA as autotaxin inhibitors., 2007; Bioorganic & medicinal chemistry. 16(5) 2212-25. PMID: 18082408 | PMCID: PMC2907913
  • Srinivasan S, Bolick DT, Lukashev D, Lappas C, Sitkovsky M, Lynch KR, Hedrick CC, Sphingosine-1-phosphate reduces CD4+ T-cell activation in type 1 diabetes through regulation of hypoxia-inducible factor short isoform I.1 and CD69., 2007; Diabetes. 57(2) 484-93. PMID: 18003758
  • Cui P, Tomsig JL, McCalmont WF, Lee S, Becker CJ, Lynch KR, Macdonald TL, Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors., 2007; Bioorganic & medicinal chemistry letters. 17(6) 1634-40. PMID: 17257836 | PMCID: NIHMS20052
  • Zhu R, Snyder AH, Kharel Y, Schaffter L, Sun Q, Kennedy PC, Lynch KR, Macdonald TL, Asymmetric synthesis of conformationally constrained fingolimod analogues--discovery of an orally active sphingosine 1-phosphate receptor type-1 agonist and receptor type-3 antagonist., 2007; Journal of medicinal chemistry. 50(25) 6428-35. PMID: 17994678 | PMCID: PMC2895489
  • Awad AS, Ye H, Huang L, Li L, Foss FW, Macdonald TL, Lynch KR, Okusa MD, Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney., 2006; American journal of physiology. Renal physiology. 290(6) F1516-24. PMID: 16403835
  • Foss FW, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, Macdonald TL, Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists., 2006; Bioorganic & medicinal chemistry. 15(2) 663-77. PMID: 17113298 | PMCID: PMC1963459
 
Inventor Bio: Kevin R. Lynch
https://med.virginia.edu/faculty/faculty-listing/krl2z/