Lewis D Pennington

Publications (7)32.57 Total impact

• Article: Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

  Lewis D Pennington, Michael D Croghan, Kelvin K C Sham, Alexander J Pickrell, Paul E Harrington, Michael J Frohn, Brian A Lanman, Anthony B Reed, Matthew R Lee, Han Xu, [......], Yang Xu, Xuxia Zhang, Michael Fiorino, Michelle Horner, Henry G Morrison, Heather A Arnett, Christopher Fotsch, Andrew S Tasker, Min Wong, Victor J Cee
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  ABSTRACT: We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.
  Bioorganic & medicinal chemistry letters 11/2011; 22(1):527-31. · 2.65 Impact Factor
• Article: 4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1

  Lewis D. Pennington, Kelvin K. C. Sham, Alexander J. Pickrell, Paul E. Harrington, Michael J. Frohn, Brian A. Lanman, Anthony B. Reed, Michael D. Croghan, Matthew R. Lee, Han Xu, Michele McElvain, Yang Xu, Xuxia Zhang, Michael Fiorino, Michelle Horner, Henry G. Morrison, Heather A. Arnett, Christopher Fotsch, Min Wong, Victor J. Cee
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  ABSTRACT: The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = −78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 μM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2–5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.Keywords: Sphingosine-1-phosphate-1 receptor agonist; peripheral lymphocyte count; immunosuppression; multiple sclerosis
  08/2011;
• Article: A unified strategy for enantioselective total synthesis of cladiellin and briarellin diterpenes: total synthesis of briarellins E and F and the putative structure of alcyonin and revision of its structure assignment.

  Olivier Corminboeuf, Larry E Overman, Lewis D Pennington
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  ABSTRACT: Enantioselective total syntheses of briarellin E (12) and briarellin F (13), as well as the structure originally proposed for the cladiellin diterpene alcyonin (10), have been realized. Comparison of the spectral data for synthetic 10, natural alcyonin, cladiellisin (33), and cladiellaperoxide (34), as well as chemical transformations of 10 and natural alcyonin, suggest that the structure of this coral metabolite is allylic peroxide 11. The unified approach detailed herein can be used to access both C4-deoxygenated and C4-oxygenated cladiellins and briarellins. The central step in these syntheses is acid-promoted condensation of (Z)-alpha,beta-unsaturated aldehydes 17 with cyclohexadienyl diols 18 to form intermediates 16 incorporating the hexahydroisobenzofuran core and five stereocenters of these marine diterpenes (Scheme 1 ).
  The Journal of Organic Chemistry 07/2009; 74(15):5458-70. · 4.45 Impact Factor
• Article: Structure-brain exposure relationships.

  Stephen A Hitchcock, Lewis D Pennington
  Journal of Medicinal Chemistry 01/2007; 49(26):7559-83. · 5.25 Impact Factor
• Article: Strategic use of pinacol-terminated Prins cyclizations in target-oriented total synthesis.

  Larry E Overman, Lewis D Pennington
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  ABSTRACT: An important objective of contemporary synthesis endeavors is the development of new transformations that rapidly evolve molecular complexity in a stereocontrolled fashion. One approach toward this goal is to combine two or more distinct reactions into a single transformation, producing a process often referred to as a sequential, tandem, cascade, or domino reaction. In this Perspective, we discuss the development of one such tandem reaction, the acid-promoted (or catalyzed) Prins-pinacol rearrangement, with particular emphasis on its implementation as the key strategic element in the total synthesis of heterocyclic and carbocyclic natural products.
  The Journal of Organic Chemistry 10/2003; 68(19):7143-57. · 4.45 Impact Factor
• Article: Enantioselective total synthesis of briarellins E and F: the first total syntheses of briarellin diterpenes.

  Olivier Corminboeuf, Larry E Overman, Lewis D Pennington
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  ABSTRACT: Enantioselective total syntheses of briarellin E (4) and briarellin F (5) have been achieved starting with (S)-(+)-carvone and (S)-(-)-glycidol. These total syntheses are the first of briarellin diterpenes. The central step in these syntheses is acid-promoted condensation of cyclohexadienyl diol 15 and (Z)-alpha,beta-unsaturated aldehyde 16 to form, with complete stereocontrol, the hexahydroisobenzofuran core and six stereocenters of these coral metabolites. These syntheses also feature stereospecific photolytic deformylation of beta,gamma-unsaturated aldehyde 17 to remove the extraneous carbon introduced in the Prins-pinacol step, chemo- and stereoselective hydroxyl-directed epoxidation of dienyl alcohol 18 to incorporate the C3 oxygen stereocenter, regio- and stereoselective rearrangement of epoxy ester 19 to install the C4 oxygen substituent, efficient dehydrative cyclization of a 1,6-diol intermediate to form the oxepane ring, and diastereoselective Nozaki-Hiyama-Kishi cyclization of vinyl iodide aldehyde 25 to forge the oxacyclononane ring and the C6 hydroxyl stereocenter. These total syntheses establish the absolute configurations of 4 and 5, define a concise strategy for the total synthesis of briarellin diterpenes, and provide additional illustrations of the uncommon utility of pinacol-terminated cationic cyclizations for stereocontrolled synthesis of complex oxacyclic natural products.
  Journal of the American Chemical Society 07/2003; 125(22):6650-2. · 9.91 Impact Factor
• Article: Total synthesis of the reputed structure of alcyonin and reassignment of its structure.

  Olivier Corminboeuf, Larry E Overman, Lewis D Pennington
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  ABSTRACT: Introduction of the C4 hydroxyl group by an epoxy ester rearrangement is a pivotal step in the first total synthesis of the purported structure of alcyonin. As the spectral data for diol acetate 3 do not match those reported for alcyonin, the structure of this marine diterpene must be revised. Reexamination of NMR spectra, MS data, and chemical transformations of natural alcyonin suggests that the structure of this marine metabolite is allylic peroxide 15.[structure: see text]
  Organic Letters 06/2003; 5(9):1543-6. · 5.86 Impact Factor