In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma

Chen, Hwang Hsing; Namil, Abdelmoulah; Severns, Bryon; Ward, Jennifer; Kelly, Curtis R.; Drace, Colene; McLaughlin, Marsha A.; Yacoub, Shenouda; Li, Byron; Patil, Raj; Sharif, Naj; Hellberg, Mark R.; Rusinko, Andrew; Pang, Iok Hou; Combrink, Keith D.

doi:10.1016/j.bmcl.2014.03.017

Cited by 17 publications

(13 citation statements)

References 24 publications

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“…Indeed, abnormal activation of ROCK has been observed in diabetic nephropathy, [21][22][23][24][25][26] cardiovascular disease, 19,24,[27][28][29][30][31] and central nervous system (CNS) diseases including Alzheimer's disease, [32][33][34] spinal cord injury, 32,[35][36][37][38] stroke, [39][40][41][42][43][44][45][46] multiple sclerosis, 32 and glaucoma. [47][48][49][50][51][52][53][54][55][56] In particular, a recent study reported that the protein level of RhoA increased in the optic nerve head of patients with primary open-angle glaucoma (POAG), 57 an effect that might lead to excessive activation of ROCK. Many studies using models such as hypertension, hyperlipidemia, and diabetes have demonstrated that ROCK activation caused elevated oxidative stress levels via NADPH oxidase (Nox), and that this was eliminated by oral administration of the ROCK inhibitor fasudil.…”

mentioning

confidence: 99%

The Novel Rho Kinase (ROCK) Inhibitor K-115: A New Candidate Drug for Neuroprotective Treatment in Glaucoma

Yamamoto¹,

Maruyama²,

Himori³

et al. 2014

Invest. Ophthalmol. Vis. Sci.

122

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confidence: 99%

The Novel Rho Kinase (ROCK) Inhibitor K-115: A New Candidate Drug for Neuroprotective Treatment in Glaucoma

Yamamoto¹,

Maruyama²,

Himori³

et al. 2014

Invest. Ophthalmol. Vis. Sci.

122

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“…3 There are two isoforms, ROCK I and II, and are involved in various physiological and pathophysiological signaling pathways. 4,5 ROCKs have been studied extensively and known as the major downstream effectors of RhoA. 6 It was involved in the generation of actin-myosin contractility and regulation of actin cytoskeleton dynamics.…”

Section: Rho Kinase (Rock)mentioning

confidence: 99%

“… 3 There are two isoforms, ROCK I and II, and are involved in various physiological and pathophysiological signaling pathways. 4 , 5 …”

Section: Introductionmentioning

confidence: 99%

<p>A Systematic Review on Rho-Kinase as a Potential Therapeutic Target for the Treatment of Erectile Dysfunction</p>

Zewdie

Ayza

Tesfaye

et al. 2020

RRU

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Background: Erectile dysfunction (ED) is a common clinical condition with limited treatment options. The main aim of the present systematic review was to synthesize information on Rho-kinase as a novel therapeutic approach for the treatment of ED. Methods: We performed a systematic literature study in PubMed, Google Scholar and Scopus. Included studies were original articles studied the role of Rho-kinase in the pathogenesis and/or new treatment approach for ED in animal models and clinical studies, published between 2014 and 2019. Data derived from each study were study design used, interventions applied and main treatment outcomes. The quality of the selected articles was assessed by CAMARADES criteria and data were analyzed using descriptive statistics. Results: A total of 1067 original articles were retrieved in the given period and eighteen papers met our inclusion criteria. Five articles explain the role of Rho-kinase in ED pathogenesis using different models such as cavernous nerve crush injury, heart failureinduced ED, vasculogenic and post-radical prostatectomy ED, diabetes-induced ED and agerelated ED. Other ten papers explain the role of novel drugs evaluated for ED treatment by targeting Rho-kinase as a new approach for ED therapy. The rest three papers discuss the role of plant extracts used by traditional society for the treatment of ED and assess their potential function in targeting Rho-kinase in animal models. The penile erectile functional index has shown that the ratio of intracavernosal pressure to mean arterial pressure (ICP/MAP) was decreased due to age and various chronic diseases. Whilst, ROCK I and ROCK II expression were increased. Western blot findings have also shown that ROCK II and MYPT-1 phosphorylation rates increased in cavernous tissue after ED induction. Besides, compounds which can inhibit the action of Rho-kinase activity showed relaxation of the corpus cavernosum, decrease in corporal fibrosis, and alleviate increased apoptosis and caspase-3 activity in an NO-independent manner. Moreover, histological and molecular dysregulation have been improved by inhibition of Rho-kinase. Conclusion: Targeting Rho-kinase may be a possible target for the treatment of ED secondary to specific causes, and Rho-kinase inhibitors may be a new drug family for the treatment of ED. However, this requires further studies for in-depth understanding.

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“…Pyridine is a second well-studied ROCK inhibitor scaffold and has likewise been subjected to extensive optimization for potency and selectivity. 124–126 R-3 (Y-27632), the first selective inhibitor for ROCKs 127 and derivatives such as R-4 (Y-39983), 128 R-5 , 126 R-6 , and R-7 129 have been examined for effects on IOP. Newer scaffolds identified via high throughput screening, such as pyrazole, indazole, aminofurazans, 2,4-diaminopyrimidines, benzodioxanes, urea derivatives and benzothiophenes, have expanded the chemical space for ROCK inhibition.…”

Section: New Therapies In Late-stage Developmentmentioning

confidence: 99%

“… a IC 50 values unless otherwise noted. b References R-1 115 , R-2 272 , R-3 109 , R-4, 119 R-5 126 , R-6, 129 R-7, 129 R-8, 109, 141 R-9, 130 R-10, 131 R-11, 156 R-12, 157 R-13 157 . c Tested in perfusion studies. N/A: not available.…”

Section: Figurementioning

confidence: 99%

Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

Donegan

Lieberman

2015

J. Med. Chem.

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Glaucoma, a heterogeneous ocular disorder affecting ~60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.

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In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma

Cited by 17 publications

References 24 publications

The Novel Rho Kinase (ROCK) Inhibitor K-115: A New Candidate Drug for Neuroprotective Treatment in Glaucoma

The Novel Rho Kinase (ROCK) Inhibitor K-115: A New Candidate Drug for Neuroprotective Treatment in Glaucoma

<p>A Systematic Review on Rho-Kinase as a Potential Therapeutic Target for the Treatment of Erectile Dysfunction</p>

Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

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