Discovery to Launch of Anti-allergy (Emadine; Patanol/Pataday/Pazeo) and Anti-glaucoma (Travatan; Simbrinza) Ocular Drugs, and Generation of Novel Pharmacological Tools Such as AL-8810

Abstract

The eye and eyesight are exquistly designed and are precious, and yet we often take them for granted. Good vision is critical for our long-term survival and for humanity's enduring progress. Unfortunately, since ocular diseases do not culminate in life-and-death scenarios, awareness of the plight of millions of people suffering from such eye ailments is not publicized as other diseases. However, losing eyesight or falling victim to visual impairment is a frightening outlook for most people. Glaucoma, a collection of chronic optic neuropathies, of which the most prevalent form, primary open-angle glaucoma (POAG), is the second leading cause of irreversible blindness. POAG currently afflicts >70 million people worldwide and is an insidious, progressive, silent thief of sight that is asymptomatic. On the other hand, allergic conjunctivitis (AC), and the associated rhinitis ("hay-fever"), frequently victimizes a huge number of people worldwide, especially during seasonal changes. While not life-threatening, sufferers of AC soon learn the value of drugs to treat their signs and symptoms of AC as they desire rapid relief to overcome the ocular itching/pain, redness, and tearing AC causes. Herein, I will describe the collective efforts of many researchers whose industrious, diligent, and dedicated team work resulted in the discovery, biochemical/pharmacological characterization, development and eventual launch of drugs to treat AC (e.g., olopatadine [Patanol/Pataday/Pazeo] and emedastine [Emedine]), and for treating ocular hypertension and POAG (e.g., travoprost [Travatan ] and Simbrinza). This represents a personal perspective.

Figure 1

Basic anatomy and structural elements of the human eye to illustrate key features discussed in this article. Panel A reproduced and modified with permission from ref (8). Copyright 2020 Springer Publishing Company. Panel B reproduced and updated with permission from ref (7). Copyright 2018 Mary Ann Liebert Publishing Inc.

Figure 2

Panel A shows the concentration-dependent stimulation of PI turnover by three key mast cell mediators in HCE cells. The antagonism of histamine-induced responses in three different human cell-types by olopatadine (AL-4943A) are displayed in panel B. Reproduced and updated with permission from refs ( and 32). Copyright 1996 and 1997 Mary Ann Liebert Publishing Inc.

Figure 3

Histamine release from isolated human conjunctival mast cells (HCMCs) exposed to an immunological challenge and the ability of olopatadine and other antiallergic drugs to inhibit the release is depicted. Figure reproduced with permission from ref (30). Copyright 1996 American Society for Pharmacology and Experimental Therapeutics.

Figure 4

Correlations of immunologic-challenge-induced secretion of histamine, tryptase (A) and PGD₂ (B), and their inhibition by different concentrations of olopatadine, from human conjunctival mast cells is shown. Figure reproduced with permission from ref (30). Copyright 1996 American Society for Pharmacology and Experimental Therapeutics.

Figure 5

This montage depicts the relative affinity and selectivity of olopatadine for H₁–H₃ receptors subtypes (A), and the ability of histamine to increase production of [³H]-IPs in isolated h-TM cells and the noncompetitive antagonism of these responses by different concentrations of olopatadine (B). Panel A reproduced with permission from ref (29). Copyright 1996 Mary Ann Liebert Publishing Inc. Panel B reproduced with permission from ref (30). Copyright 1996 American Society for Pharmacology and Experimental Therapeutics.

Figure 6

Diagram showing the generation of AQH and its inhibition by certain drugs, and drainage of AQH from the anterior chamber of the eye via two different outflow pathways as promoted by different drug classes. Reproduced and updated with permission from ref (7). Copyright 2018 Mary Ann Liebert Publishing Inc.

Figure 7

Structures of the key PG pro-drugs discussed in this article are shown in this figure.

Figure 8

(A) Autoradiographically visualized FP-receptors in a section of human eye in vitro are shown (total binding of [³H]-PGF_2α). The black/white radioautograph was pseudocolor coded to illustrate the relative density of the FP-receptors. Red indicates the highest density, followed by orange, yellow, green, and blue. (B) PI turnover and accumulation of intracellular [³H]-IPs following stimulation by fluprostenol (R/S; racemate), PGF_2α, and unoprostone free acid in HEK-943 cells expressing human cloned ciliary body FP-receptor. Reproduced with permission from ref (164). Copyright 2002 Mary Ann Liebert Publishing Inc. (C) MAP kinase activity stimulated by travoprost acid (S-enantiomer of fluprostenol) and fluprostenol (R/S; racemate) in isolated and cultivated hCM cells. Reproduced with permission from ref (162). Copyright 2003 Mary Ann Liebert Publishing Inc.

Figure 9

IOP reduction by three different PG pro-drug compounds tested t.o. at different doses in the OHT eyes of conscious cynomolgus monkeys.

Figure 10

(A,B) Concentration-dependent mobilization of [Ca²⁺]_i (A) and MMP-3 secretion from h-CM cells (B) in response to travoprost acid (AL-5848). Reproduced and updated with permission from ref (162). Coopyright 2003 Mary Ann Liebert Publishing Inc.

Figure 11

Morphological changes induced by ROCK inhibitors in h-TM cells. Reproduced with permission from ref (7). Copyright 2018 Mary Ann Liebert Publishing Inc.

Figure 12

Ability of two different classes of compounds to stimulate conventional outflow facility in isolated anterior chambers of porcine eyes. Reproduced with permission from ref (7). Copyright 2018 Mary Ann Liebert Publishing Inc.

Figure 13

Ability of different t.o. doses of the two enantiomers of a potent and selective 5-HT_2A receptor agonist (DOI) to lower and control IOP in conscious OHT cynomolgus eyes. Reproduced with permission from ref (7). Copyright 2018 Mary Ann Liebert Publishing Inc.

Figure 14

(A) Agonist potency and intrinsic activity of AL-8810 vs the full-agonist cloprostenol. (B,C) Schild analysis of the antagonist potency of AL-8810 vs fluprostenol-induced [³H]-IPs accumulation in A7r5 rat aortic cells in vitro. (D) AL-8810 concentration-dependently antagonized the functional activity of bimatoprost within a few seconds. (E) AL-8810 antagonized the functional responses to various FP-receptor agonists in a concentration-dependent manner. Overall, the antagonist potency of AL-8810 against a range of FP-agonists in various assay systems was 734 ± 228 nM. While not highly potent, it has proven very useful in clarifying the role of FP-receptors and/or endogenous and exogenous FP-receptor agonist in numerous systems in vitro and in vivo. Panels A–E are reproduced/modified with permission from refs ( and 233). Copyright 1999 American Society for Pharmacology and Experimental Therapeutics and 2019 Wiley.

Figure 15

(A) Autoradiographic localization and quantification of DP-receptors in post-mortem human eye sections determined in vitro using the highly selective DP-receptor antagonist radioligand, [³H]-BWA868C. (B) The concentration-dependent displacement of [³H]-BWA868C from DP-receptors in human eye sections in vitro by a potent and selective DP-receptor agonist (BW245C), and (C) graphic representation of such data for a number of DP-receptor agonists. NSB = nonspecific binding. Reproduced with permission from ref (273). Copyright 2005 Mary Ann Liebert Publishing Inc.

Figure 16

ATP energy depletion and restoration after hypoxia/reperfusion of human (panel A) and rat retinas (panel B) in the absence and presence of MK-801 NMDA-receptor-channel blocker as determined by ³¹P NMR spectroscopy. Reproduced with permission from ref (7). Copyright 2018 Mary Ann Liebert Publishing Inc.