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Qiaolin Deng,
Joseph A Clemas,
Gary Chrebet,
Paul Fischer,
Jeffrey J Hale,
Zhen Li,
Sander G Mills, James Bergstrom,
Suzanne Mandala,
Ralph Mosley,
Stephen A Parent
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ABSTRACT: Sphingosine-1-phosphate (S1P) receptor agonists are novel immunosuppressive agents. The selectivity of S1P1 against S1P3 is strongly correlated with lymphocyte sequestration and minimum acute toxicity and bradycardia. This study describes molecular modeling, site-directed mutagenesis, and affinity studies exploring the molecular basis for selectivity between S1P1 and S1P3 receptors. Computational models of human S1P1 and S1P3 receptors bound with two nonselective agonists or two S1P1-selective agonists were developed based on the X-ray crystal structure of bovine rhodopsin. The models predict that S1P1 Leu276 and S1P3 Phe263 contribute to the S1P1/S1P3 selectivity of the two S1P1-selective agonists. These residues were subjected to site-directed mutagenesis. The wild-type and mutant S1P receptors were expressed in Chinese hamster ovary cells and examined for their abilities to bind to and be activated by agonists in vitro. The results indicate that the mutations have minimal effects on the activities of the two nonselective agonists, although they have dramatic effects on the S1P1-selective agonists. These studies provide a fundamental understanding of how these two receptor-selective agonists bind to the S1P1 and S1P3 receptors, which should aid development of more selective S1P1 receptor agonists with immunosuppressive properties and improved safety profiles.
Molecular Pharmacology 04/2007; 71(3):724-35. · 4.88 Impact Factor
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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
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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
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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
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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
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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
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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
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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
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Jeffrey J Hale,
George Doherty,
Leslie Toth,
Zhen Li,
Sander G Mills,
Richard Hajdu,
Carol Ann Keohane,
Mark Rosenbach,
James Milligan,
Gan-Ju Shei,
Gary Chrebet, James Bergstrom,
Deborah Card,
Hugh Rosen,
Suzanne Mandala
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ABSTRACT: 3-(N-Alkyl)aminopropylphosphonic acids are potent agonists of four of the five known sphingosine-1-phosphate (S1P) receptor subtypes.
Bioorganic & Medicinal Chemistry Letters 08/2004; 14(13):3495-9. · 2.55 Impact Factor
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Jeffrey J Hale,
George Doherty,
Leslie Toth,
Sander G Mills,
Richard Hajdu,
Carol Ann Keohane,
Mark Rosenbach,
James Milligan,
Gan-Ju Shei,
Gary Chrebet, James Bergstrom,
Deborah Card,
Michael Forrest,
Shu-Yu Sun,
Sarah West,
Huijuan Xie,
Naomi Nomura,
Hugh Rosen,
Suzanne Mandala
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ABSTRACT: Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor agonists that maintain affinity for S1P1, and have decreased affinity for S1P3 are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents than do nonselective agonists.
Bioorganic & Medicinal Chemistry Letters 08/2004; 14(13):3501-5. · 2.55 Impact Factor
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Jeffrey J Hale,
William Neway,
Sander G Mills,
Richard Hajdu,
Carol Ann Keohane,
Mark Rosenbach,
James Milligan,
Gan-Ju Shei,
Gary Chrebet, James Bergstrom,
Deborah Card,
Gloria C Koo,
Sam L Koprak,
Jesse J Jackson,
Hugh Rosen,
Suzanne Mandala
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ABSTRACT: Alteration in lymphocyte trafficking and prevention of graft rejection in rodents observed on exposure to FTY720 (1) or its corresponding phosphate ester 2 can be induced by the systemic administration of potent sphingosine-1-phosphate receptor agonists exemplified by 19. The similar S1P receptor profiles of 2 and 19 coupled with their comparable potency in vivo supports a connection between S1P receptor agonism and immunosuppressive efficacy.
Bioorganic & Medicinal Chemistry Letters 07/2004; 14(12):3351-5. · 2.55 Impact Factor
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Suzanne Mandala,
Richard Hajdu, James Bergstrom,
Elizabeth Quackenbush,
Jenny Xie,
James Milligan,
Rosemary Thornton,
Gan-Ju Shei,
Deborah Card,
CarolAnn Keohane,
Mark Rosenbach,
Jeffrey Hale,
Christopher L Lynch,
Kathleen Rupprecht,
William Parsons,
Hugh Rosen
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ABSTRACT: Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.
Science 05/2002; 296(5566):346-9. · 31.20 Impact Factor
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ABSTRACT: Sphingosine and sphingosine-1-phosphate (SPP) are interconvertible sphingolipid metabolites with opposing effects on cell
growth and apoptosis. Based on sequence homology with LBP1, a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast, we report here the cloning,
identification, and characterization of a mammalian SPP phosphatase (mSPP1). This hydrophobic enzyme, which contains the type
2 lipid phosphohydrolase conserved sequence motif, shows substrate specificity for SPP. Partially purified Myc-tagged mSPP1
was also highly active at dephosphorylating SPP. When expressed in yeast, mSPP1 can partially substitute for the function
of LBP1. Membrane fractions from human embryonic kidney HEK293 cells transfected with mSPP1 markedly degraded SPP but not lysophosphatidic
acid, phosphatidic acid, or ceramide-1-phosphate. Enforced expression of mSPP1 in NIH 3T3 fibroblasts not only decreased SPP
and enhanced ceramide levels, it also markedly diminished survival and induced the characteristic traits of apoptosis. Collectively,
our results suggest that SPP phosphohydrolase may regulate the dynamic balance between sphingolipid metabolite levels in mammalian
cells and consequently influence cell fate.
Proceedings of the National Academy of Sciences 07/2000; 97(14):7859-7864. · 9.68 Impact Factor
