1. A multivalent approach towards linked dual-pharmacology prostaglandin F receptor agonist/carbonic anhydrase-II inhibitors for the treatment of glaucoma.
- Author
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Long DD, Frieman B, Hegde SS, Hill CM, Jiang L, Kintz S, Marquess DG, Purkey H, Shaw JP, Steinfeld T, Wilson MS, and Wrench K
- Subjects
- Carbonic Anhydrase Inhibitors chemistry, Drug Discovery, Humans, Models, Molecular, Prostaglandins F, Synthetic chemistry, Receptors, Prostaglandin chemistry, Carbonic Anhydrase Inhibitors pharmacology, Glaucoma drug therapy, Prostaglandins F, Synthetic pharmacology, Receptors, Prostaglandin agonists
- Abstract
Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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