Two stereoisomeric imidazoline derivatives: synthesis and optical and alpha 2-adrenoceptor activities.

Two eight-step pathways for synthesizing the stereoisomeric compounds (-)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("levlofexidine" hydrochloride; (-)-lofexidine hydrochloride) and (+)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("dexlofexidine" hydrochloride; (+)-lofexidine hydrochloride) and the optical resolution of (+/-)-lofexidine are described. (-)-Lofexidine, a stereoselective alpha 2-adrenoceptor agonist, due to its center of asymmetry, is demonstrated to be a potent drug for the treatment of hypertension (doses 0.561 microgram/kg) and to have the highest affinity and a concentration dependency for alpha 2-adrenoceptors in direct binding studies (0.36 nmol/L). (+)-Lofexidine is 10 times less potent.

Omega-[(omega-arylalkyl)aryl]alkanoic acids: a new class of specific LTA4 hydrolase inhibitors.

The synthesis and structure-activity profile of a new class of potent and specific LTA4 hydrolase inhibitors are described. Many compounds of this series of omega-[5-(omega-arylalkyl)-2-thienyl]- and omega-[4-(omega-arylalkyl)phenyl]alkanoic acids were found to be potent in vitro inhibitors of the LTB4 production by porcine leukocytes with IC50 ranging from 1 to 10 microM. The side-chain lengths were critical for an optimal activity. Substitutions on the terminal aromatic ring, in the benzene series, by lipophilic and electron-donating substituents substantially enhanced the LTA4 hydrolase inhibition potency. On the other hand, in the thiophene series, the effect of of such substitutions on the LTA4 hydrolase inhibition was rather small. Functionalization within the carboxylic acid side chain by a carbonyl or by a hydroxyl group led to less potent compounds. A metabolically stable LTA4 hydrolase inhibitor, RP64966, was obtained by insertion of an oxygen atom in the beta-position on the carboxylic acid side chain. After oral administration of RP64966 to rats, a plasma extract was found to display potent inhibition of the LTB4 biosynthesis (40% inhibition at 5 mg/kg, po).

Omega-[(omega-arylalkyl)thienyl]alkanoic acids: from specific LTA4 hydrolase inhibitors to LTB4 receptor antagonists.

A series of omega-[(omega-arylalkyl)thienyl]alkanoic acid isomers was prepared and a structure-activity relationship was investigated. These compounds have displayed either LTA4 hydrolase inhibition activities or LTB4 receptor binding activities, or both, depending on the relative orientation of the two side chains on the thiophene ring. Whereas the 2,5-isomers specifically exhibited LTA4 hydrolase inhibition, 3,5-isomers displayed both activities. On the other hand, the "ortho-isomers" specifically inhibited the binding of the LTB4 to its receptor. The side-chain lengths were also important for an optimal inhibition or binding activity. Substitutions on the terminal aromatic ring or on the thiophene nucleus led to small changes in both activities. The most dramatic effect was obtained by substituting the carboxylic acid side chain in the alpha-position with one or two methyl groups, which substantially enhanced the LTB4 receptor binding activity. In the most favorable case, the alpha,alpha-dimethyl derivative RP66153 was found 20-fold more potent than its linear counterpart.