Novel Potassium-Channel Openers: Preparation and Pharmacological Evaluation of Racemic and Optically Active N-(6-Amino-3-pyridyl)-N'-bicycloalkyl-N''-cyanoguanidine Derivatives

Abstract

The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'- [(1S,2R,4R)-bicyclo- [2.2.1]hept-2-yl]-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K(+)-channel opener, it showed different pharmacological and conformational profiles from pinacidil.

Structure-Activity Relationships of KATP Channel Openers

“…Rigid cyclic moieties like norbornyl in the terminal lipophilic region were better than alkyl chains. Later [57], the best compounds of the previous study [56] were investigated in more detail involving in particular their pure enantiomers. noguanidine was selected for development as an antihypertensive agent.…”

Chiral N-(6-Amino-3-pyridyl)-N'-bicycloalkyl-N''-cyanoguanidine Derivative: a Novel Potassium-Channel Opener

“…The title compound was synthesized according to the method of Eda et al (1994), and recrystallized from acetonitrile. The structure was solved by direct methods using SHELXS86 and expanded by Fourier techniques using DIRDIF92 (Beurskens et al, 1992).…”

Chiral linker 5: scope and limitations of arylsubstituted m-hydrobenzoins as solid supported open chain chiral auxiliaries for diastereoselective syntheses

“…The absolute configurations of the major products were assigned via the specific rotation of norbornene carboxylic acids 18. 19 Table 3 shows that although satisfactory endo selectivities were observed in the model reactions, only moderate enantiomeric purities of endo-18 could be obtained even with the most suitable auxiliary 7a. However, considering Oppolzer's model for the geometry of chiral secondary alcohol acrylates 20 under the influence of Lewis acids, the fact that in almost all experiments the (1S,2S,4S)-acid was isolated as the major product seems surprising.…”

“…)), 28.5/28.4 (O-CH 2 CH(CH 3 ) 2 (diast. )), 19.1 (O-CH 2 CH(CH 3 ) 2 ), 19.0 (Ph-CH 3 ), 16.6/16.3 (CO-CH(CH 3 )-CH 2 Ph(diast. )); M = 489.62.…”

“…endo-Selectivities and enantiomeric excesses were determined by GC analysis of methyl esters 19 and afterwards verified via comparison with values obtained from 1 H NMR integration on crude reaction mixtures 17 as well as acids 18, 18 absolute configuration of major enantiomers was approved by optical rotations of 18 19. b Reaction quenched at À80°C.…”