title: Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is one of the leading causes of loss of vision in the industrialized world. Attenuating the VEGF signal in the eye to treat AMD has been validated clinically. A large body of evidence suggests that inhibitors targeting the VEGFr pathway may be effective for the treatment of AMD. Recent studies using Src/YES knockout mice suggest that along with VEGF, Src and YES play a crucial role in vascular leak and might be useful in treating edema associated with AMD. Therefore, we have developed several potent benzotriazine inhibitors designed to target VEGFr2, Src, and YES. One of the most potent compounds is 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)phenylamino]benzo[1,2,4]triazin-7-yl}phenol ( 5), a dual inhibitor of both VEGFr2 and the Src family (Src and YES) kinases. Several ester analogues of 5 were prepared as prodrugs to improve the concentration of 5 at the back of the eye after topical administration. The thermal stability of these esters was studied, and it was found that benzoyl and substituted benzoyl esters of 5 showed good thermal stability. The hydrolysis rates of these prodrugs were studied to analyze their ability to undergo conversion to 5 in vivo so that appropriate concentrations of 5 are available in the back-of-the-eye tissues. From these studies, we identified 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotriazin-7-yl)phenyl benzoate ( 12), a topically administered prodrug delivered as an eye drop that is readily converted to the active compound 5 in the eye. This topically delivered compound exhibited excellent ocular pharmacokinetics and poor systemic circulation and showed good efficacy in the laser induced choroidal neovascularization model. On the basis of its superior profile, compound 12 was advanced. It is currently in a clinical trial as a first in class, VEGFr2 targeting, topically applied compound for the treatment of AMD.
authors.affiliation: TargeGen Inc., 9890 Judicial Drive, San Diego, CA 92121, USA. Palanki@targegen.com
authors.forename: Moorthy S S
authors.initials: MS
authors.lastname: Palanki
authors.forename: Hideo
authors.initials: H
authors.lastname: Akiyama
authors.forename: Peter
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authors.lastname: Campochiaro
authors.forename: Jianguo
authors.initials: J
authors.lastname: Cao
authors.forename: Chun P
authors.initials: CP
authors.lastname: Chow
authors.forename: Luis
authors.initials: L
authors.lastname: Dellamary
authors.forename: John
authors.initials: J
authors.lastname: Doukas
authors.forename: Richard
authors.initials: R
authors.lastname: Fine
authors.forename: Colleen
authors.initials: C
authors.lastname: Gritzen
authors.forename: John D
authors.initials: JD
authors.lastname: Hood
authors.forename: Steven
authors.initials: S
authors.lastname: Hu
authors.forename: Shu
authors.initials: S
authors.lastname: Kachi
authors.forename: Xinshan
authors.initials: X
authors.lastname: Kang
authors.forename: Boris
authors.initials: B
authors.lastname: Klebansky
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kousba
authors.forename: Dan
authors.initials: D
authors.lastname: Lohse
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Mak
authors.forename: Michael
authors.initials: M
authors.lastname: Martin
authors.forename: Andrew
authors.initials: A
authors.lastname: McPherson
authors.forename: Ved P
authors.initials: VP
authors.lastname: Pathak
authors.forename: Joel
authors.initials: J
authors.lastname: Renick
authors.forename: Richard
authors.initials: R
authors.lastname: Soll
authors.forename: Naoyasu
authors.initials: N
authors.lastname: Umeda
authors.forename: Shiyin
authors.initials: S
authors.lastname: Yee
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yokoi
authors.forename: Binqi
authors.initials: B
authors.lastname: Zeng
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Glenn
authors.initials: G
authors.lastname: Noronha
mesh_terms: D000287:Administration, Topical; D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005123:Eye / Q000187:drug effects / Q000528:radiation effects; D007834:Lasers; D008268:Macular Degeneration / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D009883:Ophthalmic Solutions / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010636:Phenols / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C529233:4-chloro-3-(5-methyl-3-((4-(2-pyrrolidin-1-ylethoxy)phenyl)amino)-1,2,4-benzotriazin-7-yl)phenol; D009883:Ophthalmic Solutions; D010636:Phenols; D011355:Prodrugs; D014227:Triazines; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases