title: Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.
abstract: 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.
authors.affiliation: Allergan Pharmaceuticals, Irvine, California 92612, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Munk
authors.forename: D
authors.initials: D
authors.lastname: Harcourt
authors.forename: G
authors.initials: G
authors.lastname: Ambrus
authors.forename: L
authors.initials: L
authors.lastname: Denys
authors.forename: C
authors.initials: C
authors.lastname: Gluchowski
authors.forename: J A
authors.initials: JA
authors.lastname: Burke
authors.forename: A B
authors.initials: AB
authors.lastname: Kharlamb
authors.forename: C A
authors.initials: CA
authors.lastname: Manlapaz
authors.forename: E U
authors.initials: EU
authors.lastname: Padillo
authors.forename: E
authors.initials: E
authors.lastname: Runde
authors.forename: L
authors.initials: L
authors.lastname: Williams
authors.forename: L A
authors.initials: LA
authors.lastname: Wheeler
authors.forename: M E
authors.initials: ME
authors.lastname: Garst
mesh_terms: 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
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles