title: Synthesis, in vitro activities of (2-cyclopropoxyphenyl)piperidine derivatives for alpha 1a and alpha 1d adrenergic receptor inhibitors.
abstract: An alpha 1a- and alpha 1d-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 alpha1a-AR and alpha1d-AR compared to alpha1b-AR and D2 receptor, Ki values for alpha1a-AR are 0.91 nM to 79.0 nM and alpha1d-AR are 2.0 nM to 57 nM; Ki values for alpha1b-AR are 107 nM to 839.8 nM and D2 receptor are 66.2 nM to 187.1 nM. The selectivity ratios of Ki(alpha1b)/Ki(alpha1a) are 11 to 155 fold, Ki(alpha1b)/Ki(alpha1d) are 6 to 171 fold, Ki(D2)/Ki(alpha1a) are 2 to 158 fold, and Ki(D2)/Ki(alpha1d) are 1.2 to 89 fold. Compound 17a shows improved stability in human liver microsome test (t1/2 = 18 minutes).
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development LLC, Drug Discovery Research, PO Box 300, 1000 Route 202 South, Raritan, NJ 08869, USA. sli3@prdus.jnj.com
authors.forename: Shengjian
authors.initials: S
authors.lastname: Li
authors.forename: George
authors.initials: G
authors.lastname: Chiu
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Pulito
authors.forename: Jingchun
authors.initials: J
authors.lastname: Liu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Connolly
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D001667:Binding, Competitive; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C547713:ADRA1A protein, human; C547719:ADRA1D protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D003521:Cyclopropanes; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1