- 2-Aminomethyl piperidines as novel urotensin-II receptor antagonists
-
A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described.
- Jin, Jian,Wang, Yonghui,Wang, Feng,Shi, Dongchuan,Erhard, Karl F.,Wu, Zining,Guida, Brian F.,Lawrence, Sarah K.,Behm, David J.,Disa, Jyoti,Vaidya, Kalindi S.,Evans, Christopher,McMillan, Lynette J.,Rivero, Ralph A.,Neeb, Michael J.,Douglas, Stephen A.
-
p. 2860 - 2864
(2008/12/22)
-
- (2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: Novel, highly selective κ opioid analgesics
-
This paper describes the synthesis and structure-activity relationships as κ opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives (8). The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60°, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and κ affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl) piperidine hydrochloride (14) and (2S)-1-[[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1- ylmethyl)piperidine hydrochloride (21) are the most κ/μ selective (respectively 6500:1 and 4100:1) and among the most potent (K(i) κ 0.24 and 0.57 nM, respectively) κ ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard κ ligand U-50488.
- Vecchietti,Giordani,Giardina,Colle,Clarke
-
p. 397 - 403
(2007/10/02)
-