James A Milligan

Publications (10)33.54 Total impact

• Article: 1,3,8-Triazaspiro[4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia.

  Petr Vachal, Shouwu Miao, Joan M Pierce, Deodial Guiadeen, Vincent J Colandrea, Matthew J Wyvratt, Scott P Salowe, Lisa M Sonatore, James A Milligan, Richard Hajdu, [......], John Athanasopoulos, Gregory Adam, Can D Akyuz, Dhirendra K Jena, Jeffrey W Lusen, Juncai Meng, Benjamin D Stein, Lei Xia, Edward C Sherer, Jeffrey J Hale
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  ABSTRACT: The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
  Journal of Medicinal Chemistry 02/2012; 55(7):2945-59. · 4.80 Impact Factor
• Article: SAR studies of 3-arylpropionic acids as potent and selective agonists of sphingosine-1-phosphate receptor-1 (S1P1) with enhanced pharmacokinetic properties.

  Lin Yan, Pei Huo, Jeffrey J Hale, Sander G Mills, Richard Hajdu, Carol A Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, Gary Chrebet, James Bergstrom, Deborah Card, Suzanne M Mandala
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  ABSTRACT: Structure-activity relationship (SAR) studies of 3-arylpropionic acids-a class of novel S1P(1) selective agonists-by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.
  Bioorganic & Medicinal Chemistry Letters 03/2007; 17(3):828-31. · 2.55 Impact Factor
• Article: Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes.

  Lin Yan, Pei Huo, George Doherty, Lesile Toth, Jeffrey J Hale, Sander G Mills, Richard Hajdu, Carol A Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, Gary Chrebet, James Bergstrom, Deborah Card, Elizabeth Quackenbush, Alexandra Wickham, Suzanne M Mandala
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  ABSTRACT: A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.
  Bioorganic & Medicinal Chemistry Letters 08/2006; 16(14):3679-83. · 2.55 Impact Factor
• Article: 2-Aryl(pyrrolidin-4-yl)acetic acids are potent agonists of sphingosine-1-phosphate (S1P) receptors.

  Lin Yan, Richard Budhu, Pei Huo, Christopher L Lynch, Jeffrey J Hale, Sander G Mills, Richard Hajdu, Carol A Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, Gary Chrebet, James Bergstrom, Deborah Card, Suzanne M Mandala
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  ABSTRACT: A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.
  Bioorganic & Medicinal Chemistry Letters 08/2006; 16(13):3564-8. · 2.55 Impact Factor
• Article: Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor.

  Petr Vachal, Leslie M Toth, Jeffrey J Hale, Lin Yan, Sander G Mills, Gary L Chrebet, Carol A Koehane, Richard Hajdu, James A Milligan, Mark J Rosenbach, Suzanne Mandala
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  ABSTRACT: Novel series of sphingosine-1-phosphate (S1P) receptor agonists were developed through a systematic SAR aimed to achieve high selectivity for a single member of the S1P family of receptors, S1P1. The optimized structure represents a highly S1P1-selective and efficacious agonist: S1P1/S1P2, S1P1/S1P3, S1P1/S1P4>10,000-fold, S1P1/S1P5>600-fold, while EC50 (S1P1) <0.2 nM. In vivo experiments are consistent with S1P1 receptor agonism alone being sufficient for achieving desired lymphocyte-lowering effect.
  Bioorganic & Medicinal Chemistry Letters 08/2006; 16(14):3684-7. · 2.55 Impact Factor
• Article: 2,5-Disubstituted pyrrolidine carboxylates as potent, orally active sphingosine-1-phosphate (S1P) receptor agonists.

  Vincent J Colandrea, Irene E Legiec, Pei Huo, Lin Yan, Jeffrey J Hale, Sander G Mills, James Bergstrom, Deborah Card, Gary Chebret, Richard Hajdu, Carol Ann Keohane, James A Milligan, Mark J Rosenbach, Gan-Ju Shei, Suzanne M Mandala
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  ABSTRACT: A series of 2,5-cis-disubstituted pyrrolidines were synthesized and evaluated as S1P receptor agonists. Compounds 15-21 were identified with good selectivity over S1P3 which lowered circulating lymphocytes after oral administration in mice.
  Bioorganic & Medicinal Chemistry Letters 07/2006; 16(11):2905-8. · 2.55 Impact Factor
• Article: Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3.

  Zhen Li, Weirong Chen, Jeffrey J Hale, Christopher L Lynch, Sander G Mills, Richard Hajdu, Carol Ann Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, [......], Stephen A Parent, James Bergstrom, Deborah Card, Michael Forrest, Elizabeth J Quackenbush, L Alexandra Wickham, Hugo Vargas, Rose M Evans, Hugh Rosen, Suzanne Mandala
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  ABSTRACT: A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
  Journal of Medicinal Chemistry 11/2005; 48(20):6169-73. · 5.25 Impact Factor
• Article: A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists.

  Jeffrey J Hale, Christopher L Lynch, William Neway, Sander G Mills, Richard Hajdu, Carol Ann Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, Stephen A Parent, Gary Chrebet, James Bergstrom, Deborah Card, Marc Ferrer, Peter Hodder, Berta Strulovici, Hugh Rosen, Suzanne Mandala
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  ABSTRACT: Moderately potent, selective S1P(1) receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P(1) agonists represented by 7. Many of the new compounds are potent S1P(1) agonists that select against the S1P(2), S1P(3), and S1P(4) (although not S1P(5)) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.
  Journal of Medicinal Chemistry 01/2005; 47(27):6662-5. · 5.25 Impact Factor
• Article: Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors.

  Lin Yan, Jeffrey J Hale, Christopher L Lynch, Richard Budhu, Amy Gentry, Sander G Mills, Richard Hajdu, Carol Ann Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, Gary Chrebet, James Bergstrom, Deborah Card, Hugh Rosen, Suzanne M Mandala
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  ABSTRACT: A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.
  Bioorganic & Medicinal Chemistry Letters 11/2004; 14(19):4861-6. · 2.55 Impact Factor
• Article: Synthesis, stereochemical determination and biochemical characterization of the enantiomeric phosphate esters of the novel immunosuppressive agent FTY720.

  Jeffrey J Hale, Lin Yan, William E Neway, Richard Hajdu, James D Bergstrom, James A Milligan, Gan-Ju Shei, Gary L Chrebet, Rosemary A Thornton, Deborah Card, Mark Rosenbach, HughRosen, Suzanne Mandala
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  ABSTRACT: The novel immunosuppressive agent FTY720 (1) is phosphorylated in vivo in a variety of species yielding an active metabolite that is an agonist of four of the five known G-protein-coupled sphingosine-1-phosphate (S1P) receptors. A synthesis amenable to producing gram quantities of the stereoisomeric phosphate esters, a determination of their absolute stereochemistry via an enantioselective synthesis and their characterization as S1P receptor agonists and antagonists is reported.
  Bioorganic & Medicinal Chemistry 10/2004; 12(18):4803-7. · 2.92 Impact Factor