title: Molecular design to enhance the penetration into the retina via ocular instillation.
abstract: To investigate the molecular design of drugs that have good penetration into the retina from anterior segment of the eye via ocular instillation, we optimized the length of methoxyethylene glycol chain (mEG) in the P3 region of an oral bioavailable calpain inhibitor SNJ-1945 (2) as a model compound. Modulation of the mEG length led to the optimal balance between hydrophilicity and lipophilicity and provided the compound with higher retinal exposure via ocular instillation. Incorporation of a mEG moiety would be a useful and convenient approach to attain high intraocular penetration.
authors.affiliation: Senju Pharmaceutical Co., Ltd, Research Laboratories, 1-5-4 Murotani, Nishi-ku, Kobe, Hyogo 651-2241, Japan. shirasaki@senju.co.jp
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shirasaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Masazumi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002219:Carbamates / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D015394:Molecular Structure; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; D002219:Carbamates; D004791:Enzyme Inhibitors; D002154:Calpain