- Structure-Activity relationships and molecular modeling of sphingosine kinase inhibitors
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The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention.
- Baek, Dong Jae,MacRitchie, Neil,Anthony, Nahoum G.,MacKay, Simon P.,Pyne, Susan,Pyne, Nigel J.,Bittman, Robert
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- In vitro SAR of pyrrolidine-containing histamine H3 receptor antagonists: Trends across multiple chemical series
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Structure-activity relationships (SAR) were analyzed within a library of diverse yet simple compounds prepared as histamine H3 antagonists. The libraries were constructed with a variety of low molecular weight pyrrolidines, selected from (R)-2-methylpyrrolidine, (S)-2-methylpyrrolidine, and pyrrolidine.
- Nersesian, Diana L.,Black, Lawrence A.,Miller, Thomas R.,Vortherms, Timothy A.,Esbenshade, Timothy A.,Hancock, Arthur A.,Cowart, Marlon D.
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p. 355 - 359
(2008/04/03)
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- Synthesis and Pharmacological Studies of 4,4-Disubstituted Piperidines: A New Class of Compounds with Potent Analgesic Properties
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A series of 4,4-disubstituted piperidines has been synthesized and evaluated for analgesic activity.Several of these analogues show analgesic potency comparable to morphine in the mouse writhing and tail-flick tests.A number of compounds exhibit high affi
- Huegi, Bruno S.,Ebnoether, Anton M.,Rissi, Erwin,Gadient, Fulvio,Hauser, Daniel,et al.
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