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Synthesis, In Vitro Activities of (2-Cyclopropoxyphenyl)piperidine Derivatives for α1a and α1d Adrenergic Receptor Inhibitors

[ Vol. 5 , Issue. 1 ]


Shengjian Li, George Chiu, Virginia L. Pulito, Jingchun Liu, Peter J. Connolly and Steven A. Middleton   Pages 15 - 22 ( 8 )


An α1a – and α1d – adrenergic receptor (AR) selective antagonist may be a more efficacious treatment for BPH/LUTS patients and may have fewer side effects than the existing pharmaceuticals. A facile synthesis for a series of (2-cyclopropoxyphenyl)piperidine derivatives has been developed, in which aryl vinyl ether formation and subsequent cyclopropyl formation provide efficient access to key intermediate N-Boc-4-(2-cyclopropoxyphenyl)piperidine. The synthesized (2-cyclopropoxyphenyl)piperidine derivatives display high affinity and selectivity for α1a – AR and α1d – AR compared to α1b-AR and D2 receptor, Ki values for α1a-AR are 0.91 nM to 79.0 nM and α1d-AR are 2.0 nM to 57 nM; Ki values for α1b-AR are 107 nM to 839.8 nM and D2 receptor are 66.2 nM to 187.1 nM. The selectivity ratios of Ki(α1b)/Ki(α1a) are 11 to 155 fold, Ki(α1b)/Ki(α1d) are 6 to 171 fold, Ki(D2)/Ki(α1a) are 2 to 158 fold, and Ki(D2)/Ki(α1d) are 1.2 to 89 fold. Compound 17a shows improved stability in human liver microsome test (t1/2 = 18 minutes).


Synthesis, piperidine Derivatives, Receptor Inhibitors, microsome test, 8-methoxyfluoroquinolone


Johnson&Johnson Pharmaceutical Research and Development LLC, Drug Discovery Research, PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA.

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