Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
Munk
S A
SA
Allergan Pharmaceuticals, Irvine, California 92612, USA.
Harcourt
D
D
Ambrus
G
G
Denys
L
L
Gluchowski
C
C
Burke
J A
JA
Kharlamb
A B
AB
Manlapaz
C A
CA
Padillo
E U
EU
Runde
E
E
Williams
L
L
Wheeler
L A
LA
Garst
M E
ME
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D011817:Rabbits; D013329:Structure-Activity Relationship
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles