Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI) (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2009
Serotonin and norepinephrine reuptake inhibitors SNRI Norepinephrine reuptake inhibitors NRI Serotonin reuptake inhibitor SRI Monoamine reuptake inhibitors a b s t r a c t A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
Bioorganic & Medicinal Chemistry Letters, 2009
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC 50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
Bioorganic & Medicinal Chemistry Letters, 2011
Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC 50 6 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.
Bioorganic & Medicinal Chemistry, 2001
We previously disclosed the discovery of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3) as a novel class of dopamine transporter (DAT) inhibitors and showed that ( AE)-3 has a significant functional antagonism against cocaine in vitro. Our previous preliminary structure-activity relationship study led to identification of a more potent DAT inhibitor [(AE )-4] but this compound failed to show any significant functional antagonism. To search for more potent analogues than 3 but still displaying significant functional antagonism, further SARs, molecular modeling studies and in vitro pharmacological evaluation of this novel class of DAT inhibitors were performed. Sixteen new analogues were synthesized in racemic form and evaluated as DAT inhibitors. It was found that seven new analogues are reasonably potent DAT inhibitors with K i values of 0.041-0.30 and 0.052-0.16 mM in [ 3 H]mazindol binding and inhibition of DA reuptake. Chiral isomers of several potent DAT inhibitors were obtained through chiral HPLC separation and evaluated as inhibitors at all the three monoamine transporter sites. In general, the (À)-isomer is more active than the (+)-isomer in inhibition of DA reuptake and all the (À)-isomers are selective inhibitors at the DAT site. Evaluation of cocaine's effect on dopamine uptake in the presence and absence of (+)-3 and (À)-3 showed that (À)-3 is responsible for the functional antagonism obtained with the original lead ( AE)-3. Out of the new compounds synthesized, analogue (AE )-20, which is 8-and 3-fold more potent than (AE )-3 in binding and inhibition of DA reuptake, appeared to have improved functional antagonism as compared to (AE )-3. #
Bioorganic & Medicinal Chemistry Letters, 2005
The biological screening of a collection of nature occurring diterpenoids against 11b-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi-synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11b-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC 50 (human 11b-HSD1) ¼ 9.4 nM and selectivity index (human 11b-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11b-HSD1 were generated using docking simulations. Based on the results, the structuraleactivity relationships (SARs) of compounds 1b and 2 were also discussed.