Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate

Druzgala, Pascal; Hochhaus, Günther; Bodor, Nicholas

doi:10.1016/0960-0760(91)90120-t

Cited by 91 publications

(57 citation statements)

References 11 publications

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“…In the literature, the soft drug strategy has been successfully exploited for topically applied drugs. With regard to the field of anti-inflammatory corticosteroids, attention was paid to carboxylic (thio)ester derivatives and the development of related plasma labile soft drugs 67,68 or "antedrugs". 69,70 In the dermatologic field, boron-containing type 4 phosphodiesterase inhibitors, developed for topical treatment of psoriasis and atopic dermatitis, have been successfully derivatized by incorporation of a cleavable ester group, thus weakening their systemic side effects.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

et al. 2012

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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure−activity and structure−property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC 50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

et al. 2012

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“…Competitive binding studies with rat lung type II GRs confirmed that binding affinity of LE was more than 4 times that of Dexamerhasone [77]. A vasoconstriction test in humans used to assess the bioavailability exhibited that LE could produce a blanching response similar to that of Betamethasone 17-valerate (16) to confirm its good penetration properties and strong potency [11].…”

Section: Loteprednol Etabonate (41) and Its Clinical Investigations Imentioning

confidence: 99%

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review

Chowdhury¹,

Borah²

2012

Glucocorticoids - New Recognition of Our Familiar Friend

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“…77 The pharmacokinetic profi le of LE indicates that, when absorbed systemically, it is rapidly transformed to the inactive 17 ␤ -carboxylic acid metabolite and eliminated from the body mainly through the bile and urine. 78 , 79 , 81 LE did not effect IOP in rabbits, 91 and later, various human studies ( Figure 13 ) 92 also confi rmed that it has no effect on IOP.…”

Section: E829mentioning

confidence: 99%

“…LE resulted from a classic inactive metabolite-based SD approach that used cortienic acid as starting point ( Figure 10 ). [74][75][76][77][78][79][80][81] Hydrocortisone is known to undergo a variety of oxidative and reductive metabolic conversions. 82 Oxidation of its dihydroxyacetone side chain leads to formation of cortienic acid through a 21-aldehyde (21-dehydrocortisol) and a 21-acid (cortisolic acid).…”

Section: First-generation Cortienic Acid-based Soft Steroids: Loteprementioning

confidence: 99%

Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems

Bodor

Buchwald²

2005

AAPS J

104

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A BSTRACTDespite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tearfl ow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifi cally developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specifi c effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifi cally designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on ␤ -adrenergic agonists and anti-infl ammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specifi c drug design approaches.K EYWORDS: beta-blockers , corticosteroids , eye-targeted delivery , glaucoma , intraocular pressure , oxime OCULAR DRUG DESIGN AND DELIVERY: CHALLENGESFor the therapeutic treatment of most ocular problems, topical administration clearly seems the preferred route, because for systemically administered drugs, only a very small fraction of their total dose will reach the eye from the general circulatory system. Even for this fraction, distribution to the inside of the eye is further hindered by the blood-retinal barrier (BRB), which is almost as effective as the blood-brain barrier (BBB) in restricting the passage of xenobiotics from the blood stream. 1 At fi rst sight, the eye seems an ideal, easily accessible target organ for topical treatment. However, the eye is, in fact, well protected against absorption of foreign materials, fi rst by the eyelids and tear-fl ow and then by the cornea, which forms the physical-biological barrier. When any foreign material or medication is introduced on the surface of the eye, the tear-fl ow immediately increases and washes it away in a relatively short time. Under normal conditions, the eye can accommodate only a very small volume without overfl owing. Commercial eyedrops have a volume of ~30 L, which is about the volume of the conjunctival sac in humans; however, after a single blink, only an estimated 10 L remains. 2 Consequently, there is a window of only ~5 to 7 minutes for any topically introduced drug to be absorbed, and in many cases, no more than 2% of the medication introduced to the eye will actually be absorbed. 2-4 The rest will be washed away and absorbed through the nasolacrimal duct and the mucosal membranes of the nasa...

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Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate

Cited by 91 publications

References 11 publications

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review

Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems

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