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Design and Synthesis of Conformationally Constrained 3-(N-alkylamino)propylphosphonic Acids as...
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2005 Receptor binding activity X 0280 Design and Synthesis of Conformationally Constrained 3-(N-alkylamino)propyl- phosphonic Acids as Potent Agonists of Sphingosine-1-phosphate (S1P) Recep- tors. — Analogues of 3-(N-tetradecylamino)propylphosphonic acid, a potent agonist of S1P receptors, in which the nitrogen and a neighboring carbon atom or a pair of ad- jacent carbons are tethered with short alkyl chains are synthesized to identify novel scaffolds for S1P receptor agonists. Three different scaffolds are tolerated for S1P re- ceptor agonists. Further investigations show that the proper incorporation of a phenyl ring into the long alkyl chains significantly enhances their binding affinities and pyr- rolidines (I) and (II) induce a maximal peripheral lowering of lymphocytes. Pyrro- lidines (I), (II), and cyclohexane (IV) possess greatly enhanced affinity for S1P1 as compared to their n-alkyl counterparts, and pyrrolidine (III) and cyclohexane (IV) re- veal 30 and 50-fold selectivity of S1P1 over S1P3, respectively. — (YAN*, L.; et al.; Bioorg. Med. Chem. Lett. 14 (2004) 19, 4861-4866; Dep. Med. Chem., Merck Res. Lab., Rahway, NJ 07065, USA; Eng.) — H. Hoennerscheid 01- 205
Transcript of Design and Synthesis of Conformationally Constrained 3-(N-alkylamino)propylphosphonic Acids as...
2005
Receptor binding activityX 0280 Design and Synthesis of Conformationally Constrained 3-(N-alkylamino)propyl-
phosphonic Acids as Potent Agonists of Sphingosine-1-phosphate (S1P) Recep-tors. — Analogues of 3-(N-tetradecylamino)propylphosphonic acid, a potent agonist of S1P receptors, in which the nitrogen and a neighboring carbon atom or a pair of ad-jacent carbons are tethered with short alkyl chains are synthesized to identify novel scaffolds for S1P receptor agonists. Three different scaffolds are tolerated for S1P re-ceptor agonists. Further investigations show that the proper incorporation of a phenyl ring into the long alkyl chains significantly enhances their binding affinities and pyr-rolidines (I) and (II) induce a maximal peripheral lowering of lymphocytes. Pyrro-lidines (I), (II), and cyclohexane (IV) possess greatly enhanced affinity for S1P1 as compared to their n-alkyl counterparts, and pyrrolidine (III) and cyclohexane (IV) re-veal 30 and 50-fold selectivity of S1P1 over S1P3, respectively. — (YAN*, L.; et al.; Bioorg. Med. Chem. Lett. 14 (2004) 19, 4861-4866; Dep. Med. Chem., Merck Res. Lab., Rahway, NJ 07065, USA; Eng.) — H. Hoennerscheid
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