title: Effects of novel ethacrynic acid derivatives on human trabecular meshwork cell shape, actin cytoskeletal organization, and transcellular fluid flow.
abstract: To determine efficacy and therapeutic index in the context of ocular hypotensive activity of the new ethacrynic acid (ECA) derivatives of the series (SA8,248 and SA8,389), 9,000 series (SA9,000, SA9,622 and SA9,995) and ticrynafen, we undertook a comparative evaluation of the dose-dependent effects of these compounds on human trabecular meshwork (HTM) cell shape, actin cytoskeletal organization, focal adhesions and transcellular fluid flow. Responses were either scored using an arbitrary scale of 1-5 or quantified. Compounds of the 9000 series (SA9,995>SA9,000>SA9,622) were found to be 14- to 20-fold more potent than ECA, ticrynafen or analogs from the 8,000 series (SA8,389>SA8,248) in terms of ability to induce cell shape alterations in HTM cells. Similarly, compounds of the 9,000 series (SA9,995>SA9,622>SA9,000) were found to be much stronger (2 to 20 fold) than ECA, ticrynafen or analogs of the 8000 series in terms of affecting decreases in actin stress fiber content in HTM cells. Analogs of the 9000 series (SA9,622>SA9,995>SA9,000) were also observed to be 8 to 10 fold more potent than ECA (SA8,389>ECA>SA8,248>ticrynafen) at eliciting decreases in cellular focal adhesions. Interestingly, analogs of the 9000 series (SA9,000>SA9,622>SA9,995) and SA8,248 demonstrated a huge increase (by many folds) in transcellular fluid flow of HTM cell monolayers as compared to ECA and ticrynafen. Collectively, these analyses revealed that the structural modification of ECA improves its ocular hypotensive efficacy, indicating that the SA9,000 series compounds might be promising novel ocular hypotensive drugs.
authors.affiliation: Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Ponugoti Vasantha
authors.initials: PV
authors.lastname: Rao
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimazaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Linda
authors.initials: L
authors.lastname: Franse-Carman
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Alvarado
authors.forename: David L
authors.initials: DL
authors.lastname: Epstein
mesh_terms: D000199:Actins / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D001082:Aqueous Humor / Q000187:drug effects* / Q000502:physiology; D018929:Cell Culture Techniques; D048430:Cell Shape / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D004232:Diuretics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004976:Ethacrynic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D022001:Focal Adhesions / Q000187:drug effects; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D015814:Ocular Hypotension / Q000188:drug therapy; D012590:Sclera / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013989:Ticrynafen / Q000494:pharmacology; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000199:Actins; D002934:Cinnamates; D004232:Diuretics; C496163:SA9000; D013989:Ticrynafen; D004976:Ethacrynic Acid