New Biologically Active Pregnan-21-Oic Acid Esters

Laurent, Henry; Gerhards, E; Wiechert, Rudolf

doi:10.1016/b978-0-08-019682-4.50011-1

Cited by 3 publications

(5 citation statements)

References 6 publications

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“…The methyl, ethyl, propyl, and butyl esters [E16-1,1 (9), E16-1,2 (10), E16-1,3 (11), and E16-1,4 (13)] were prepared by reacting 8 with the appropriate alcohol in the presence of SOCl 2 ; the isopropyl, neopentyl, monofluoro-, difluoro-and trifluoroethyl esters [E16-1,3i (12), E16-1,5neo ( 14), E16-1,2F 1 (16), E16-1,2F 2 (17), and E16-1,2F 3 (18)] were prepared by reacting 8 with the appropriate alcohol in the presence of pTsOH. The vinyl ester, E16-1,2vin (15), was prepared from 8 through a vinyl-exchange reaction with vinyl propionate and PdCl 2-LiCl as catalyst.…”

Section: Chemistrymentioning

confidence: 99%

“…The parent carboxylic acids do not bind to the glucocorticoid receptor and are biologically inert, while their corresponding esters bind to the glucocorticoid receptor with high affinity. [15][16][17] The esters are rapidly hydrolyzed to the hormonally inactive parent steroidal carboxylic acid by ubiquitous esterases. Consequently, their effect is localized to the area of the skin to which they are applied because their rapid inactivation prevents systemic action.…”

Section: Introductionmentioning

confidence: 99%

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Estradiol-16α-carboxylic Acid Esters as Locally Active Estrogens

2001

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We attempted to design analogues of estradiol to act as locally active estrogens without significant systemic action. We synthesized a series of 16alpha-carboxylic acid substituted steroids and their esters and tested their action in several assays of estrogenic action, including estrogen receptor (ER) binding, estrogenic potency in Ishikawa cells (human endometrial carcinoma), rat uterine weight (systemic action), and mouse vaginal reductases (local action). All of the estradiol substituted carboxylic acids (formic, acetic and propionic acids) were devoid of estrogenic action. To the contrary, many of the esters had marked estrogenic potency in the receptor and the Ishikawa assays. The esters of the 16alpha-formic acid series had the highest ER affinity with little difference between the straight-chain alcohol esters (from methyl to n-butyl). However, estrogenic action in the Ishikawa assay decreased precipitously with esters longer than the ethyl ester. This decrease correlated well with the increased rate of esterase hydrolysis of longer esters as determined in incubations with rat hepatic microsomes. The most promising candidates, the methyl, ethyl, and fluoroethyl esters of the formate series, were tested for systemic and local action in the in vivo models. All three, especially the fluoroethyl ester, showed divergence between systemic and local estrogenic action. These metabolically labile estrogens will be extremely useful for the therapeutic treatment of the vaginal dyspareunia of menopause in women for whom systemic estrogens are contraindicated.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Estradiol-16α-carboxylic Acid Esters as Locally Active Estrogens

2001

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“…Limited systemic activity is achieved by rapid catabolism into inactive products in tissues and blood. Most “soft drugs” are characterized by the presence of an ester group that can be hydrolyzed to an inactive or rapidly inactivatable compound. − …”

Section: Introductionmentioning

confidence: 99%

Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing. A Preliminary Study

et al. 2009

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New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2's ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.

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“…These oxime or alkyloxime derivatives exist in alternative Z (syn) or E (anti) configuration. They are enzymatically hydrolyzed within the eye by enzymes located in the iris-ciliary body, and subsequently, reductive enzymes also located in the iris-ciliary body (198) and the intermediate ketones (199) are inactive; they are enzymatically converted into the active S-(À) b-adrenergic blocker alcohols (200) in a site-and stereospecific manner.…”

Section: 2mentioning

confidence: 99%

“…Metabolism studies on fluocortolone revealed a number of oxidative and reductive metabolites in human urine [198] including fluocortolone-21-acid, an inactive metabolite. Synthesis and pharmacological evaluation of its different ester derivatives yielded fluocortin butyl (47, Vaspit Ò , Novoderm Ò , Varlane Ò ), the butyl ester of a C-21 carboxy steroid [199][200][201][202]. The ester is an anti-inflammatory agent of rather weak activity, and any portion absorbed systemically following topical application is hydrolyzed into inactive species.…”

Section: Softmentioning

confidence: 99%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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New Biologically Active Pregnan-21-Oic Acid Esters

Cited by 3 publications

References 6 publications

Estradiol-16α-carboxylic Acid Esters as Locally Active Estrogens

Estradiol-16α-carboxylic Acid Esters as Locally Active Estrogens

Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing. A Preliminary Study

Retrometabolism‐Based Drug Design and Targeting

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