Molecular design to enhance the penetration into the retina via ocular instillation.
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.
Shirasaki
Yoshihisa
Y
Senju Pharmaceutical Co., Ltd, Research Laboratories, 1-5-4 Murotani, Nishi-ku, Kobe, Hyogo 651-2241, Japan. shirasaki@senju.co.jp
Takahashi
Hiroaki
H
Yamaguchi
Masazumi
M
Inoue
Jun
J
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
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