title: A multivalent approach towards linked dual-pharmacology prostaglandin F receptor agonist/carbonic anhydrase-II inhibitors for the treatment of glaucoma.
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.
authors: Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA. dlong@theravance.com
authors: Daniel D
authors: DD
authors: Long
authors: Bryan
authors: B
authors: Frieman
authors: Sharath S
authors: SS
authors: Hegde
authors: Craig M
authors: CM
authors: Hill
authors: Lan
authors: L
authors: Jiang
authors: Samuel
authors: S
authors: Kintz
authors: Daniel G
authors: DG
authors: Marquess
authors: Hans
authors: H
authors: Purkey
authors: Jeng-Pyng
authors: JP
authors: Shaw
authors: Tod
authors: T
authors: Steinfeld
authors: Michael S
authors: MS
authors: Wilson
authors: Kevin
authors: K
authors: Wrench
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D005901:Glaucoma / Q000188:drug therapy*; D006801:Humans; D008958:Models, Molecular; D011461:Prostaglandins F, Synthetic / Q000737:chemistry / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000737:chemistry
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor