Design, Synthesis, and Evaluation of NO-Donor Containing Carbonic Anhydrase Inhibitors To Lower Intraocular Pressure

Huang, Qinhua; Rui, Eugene; Cobbs, Morena; Dinh, Dac M.; Gukasyan, Hovhannes J.; Lafontaine, Jennifer; Mehta, Saurabh; Patterson, Brian D.; Rewolinski, David A.; Richardson, Paul; Edwards, Martin P.

doi:10.1021/acs.jmedchem.5b00043

Cited by 24 publications

(7 citation statements)

References 23 publications

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“…Using such sections for metabolite identification and detection is feasible when standard materials are available (i.e., the metabolism is already known). Successful examples of in vivo ocular metabolism examples include, but are not limited to, tafluprost (Fukano and Kawazu, 2009), nepafenac (Chastain et al, 2016), and carbonic anhydrase prodrugs (Huang et al, 2015). Although the in vivo quantitation of metabolites can be helpful for physiologically based PK modeling of the data (if needed), its utility is limited due to the low doses and the need for high specific activity of radiolabeled compounds.…”

Section: In Vitro Models Of Ocular Metabolismmentioning

confidence: 99%

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

et al. 2018

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The eye is a complex organ with a series of anatomic barriers that provide protection from physical and chemical injury while maintaining homeostasis and function. The physiology of the eye is multifaceted, with dynamic flows and clearance mechanisms. This review highlights that in vitro ocular transport and metabolism models are confined by the availability of clinically relevant absorption, distribution, metabolism, and excretion (ADME) data. In vitro ocular transport models used for pharmacology and toxicity poorly predict ocular exposure. Although ocular cell lines cannot replicate in vivo conditions, these models can help rank-order new chemical entities in discovery. Historic ocular metabolism of small molecules was assumed to be inconsequential or assessed using authentic standards. While various in vitro models have been cited, no single system is perfect, and many must be used in combination. Several studies document the use of laboratory animals for the prediction of ocular pharmacokinetics in humans. This review focuses on the use of human-relevant and human-derived models which can be utilized in discovery and development to understand ocular disposition of new chemical entities. The benefits and caveats of each model are discussed. Furthermore, ADME case studies are summarized retrospectively and capture the ADME data collected for health authorities in the absence of definitive guidelines. Finally, we discuss the novel technologies and a hypothesis-driven ocular drug classification system to provide a holistic perspective on the ADME properties of drugs administered by the ocular route.

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Section: In Vitro Models Of Ocular Metabolismmentioning

confidence: 99%

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

et al. 2018

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“…The design strategy utilized The OHTN primate tonometry revealed significant improve- ment in efficacy, indicating the potential of dual mechanism inhibitors as IOP-lowering agents (Figure 37). 289 3.2.2. ROCK and LIM Kinase Inhibitors.…”

Section: Recent Medicinal Chemistry Campaigns For Ocular Drug Discove...mentioning

confidence: 99%

Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye

et al. 2020

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The ocular drug discovery field has evidenced significant advancement in the past decade. The FDA approvals of Rhopressa, Vyzulta, and Roclatan for glaucoma, Brolucizumab for wet age-related macular degeneration (wet AMD), Luxturna for retinitis pigmentosa, Dextenza (0.4 mg dexamethasone intracanalicular insert) for ocular inflammation, ReSure sealant to seal corneal incisions, and Lifitegrast for dry eye represent some of the major developments in the field of ocular therapeutics. A literature survey also indicates that gene therapy, stem cell therapy, and target discovery through genomic research represent significant promise as potential strategies to achieve tissue repair or regeneration and to attain therapeutic benefits in ocular diseases. Overall, the emergence of new technologies coupled with first-in-class entries in ophthalmology are highly anticipated to restructure and boost the future trends in the field of ophthalmic drug discovery. This perspective focuses on various aspects of ocular drug discovery and the recent advances therein. Recent medicinal chemistry campaigns along with a brief overview of the structure–activity relationships of the diverse chemical classes and developments in ocular drug delivery (ODD) are presented.

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“…Further research is required to determine its neuroprotective efficacy and the mechanisms involved. There are several additional NO-donor compounds that exhibit pre-clinical efficacy for IOP reduction in animal models, including the prostaglandin analogue NCX 470 and two novel carbonic anhydrase inhibitors: NO-dorzolamide and NO-brinzolamide 228, 229230 . Together, these studies indicate that NO-donor compounds are viable and potentially potent therapeutic agents for IOP lowering in glaucoma patients as well as those with ocular hypertension.…”

Section: The No-gc-1-cgmp Pathway As a Target For Glaucoma Therapeuticsmentioning

confidence: 99%

The nitric oxide-guanylate cyclase pathway and glaucoma

2018

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Glaucoma is a prevalent optic neuropathy characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs) and their optic nerve axons, which leads to irreversible visual field loss. Multiple risk factors for the disease have been identified, but elevated intraocular pressure (IOP) remains the primary risk factor amenable to treatment. Reducing IOP however does not always prevent glaucomatous neurodegeneration, and many patients progress with the disease despite having IOP in the normal range. There is increasing evidence that nitric oxide (NO) is a direct regulator of IOP and that dysfunction of the NO-Guanylate Cyclase (GC) pathway is associated with glaucoma incidence. NO has shown promise as a novel therapeutic with targeted effects that: 1) lower IOP; 2) increase ocular blood flow; and 3) confer neuroprotection. The various effects of NO in the eye appear to be mediated through the activation of the GC- guanosine 3:5'-cyclic monophosphate (cGMP) pathway and its effect on downstream targets, such as protein kinases and Ca channels. Although NO-donor compounds are promising as therapeutics for IOP regulation, they may not be ideal to harness the neuroprotective potential of NO signaling. Here we review evidence that supports direct targeting of GC as a novel pleiotrophic treatment for the disease, without the need for direct NO application. The identification and targeting of other factors that contribute to glaucoma would be beneficial to patients, particularly those that do not respond well to IOP-dependent interventions.

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Design, Synthesis, and Evaluation of NO-Donor Containing Carbonic Anhydrase Inhibitors To Lower Intraocular Pressure

Cited by 24 publications

References 23 publications

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye

The nitric oxide-guanylate cyclase pathway and glaucoma

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