Action of Some Steroids on the Central Nervous System of the Mouse. I. Synthetic Methods

Cocker, J. D.; Elks, J.; May, Paul J.; Nice, F A; Phillipps, G. H.; Wall, W F

doi:10.1021/jm00328a003

Cited by 14 publications

(9 citation statements)

References 1 publication

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“…33 mp 152-153 °C; lit. 34 mp 153-154 °C); IR (KBr) 2942, 1711, 1382, 1351 cm -1 ; 1 H NMR (CDCl3) δ 2.54 (1H, t, J ) 9.0 Hz), 2.12 (3H, s), 1.02 (3H, s), 0.81 (3H, d, J ) 6.6 Hz), 0.63 (3H, s); 13 Steroid 6b was obtained as a white solid: mp 102-104 °C (lit. 34 mp 99-102 °C); 1 H NMR (CDCl3) δ 2.57 (1H, t, J ) 9.0 Hz), 2.13 (3H, s), 1.02 (3H, s), 0.79 (3H, d, J ) 6.9 Hz), 0.63 (3H, s); 13 C NMR (CDCl3) δ 213.36, 209.52, 63.55, 56.35, 49.46, 44.11, 40.12, 38.86, 36.83, 36.59, 35.54, 35.36, 33.61, 31.32, 29.26, 24.13, 22.67, 22.55, 20.96, 19.06, 13.22.…”

Section: Methodsmentioning

confidence: 99%

Neurosteroid Analogues. 10. The Effect of Methyl Group Substitution at the C-6 and C-7 Positions on the GABA Modulatory and Anesthetic Actions of (3α,5α)- and (3α,5β)-3-Hydroxypregnan-20-one

et al. 2005

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The planar 5alpha-reduced steroid (3alpha,5alpha)-3-hydroxypregnan-20-one and the nonplanar 5beta-reduced steroid (3alpha,5beta)-3-hydroxypregnan-20-one act at GABA(A) receptors to induce general anesthesia. The structural features of the binding sites for these anesthetic steroids on GABA(A) receptors have not been determined. To determine how structural modifications at the steroid C-6 and C-7 positions effect the actions of these anesthetic steroids, an axial or equatorial methyl group was introduced at these positions. The analogues were evaluated (1) in [(35)S]-tert-butylbicyclophosphorothionate binding experiments, (2) in electrophysiological experiments using rat alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes, and (3) as tadpole anesthetics. The effects of methyl group substitution in the 5alpha- and 5beta-reduced series of compounds were strikingly similar. In both series, a 6beta-Me group gave compounds with actions similar to or greater than those of the parent steroids. A 6alpha-, 7beta- or 7alpha-Me substituent resulted in reduced potency for inhibition of radioligand binding, GABA(A) receptor modulation and tadpole anesthesia. Because of the similar effects of methyl group substitution in the two series of compounds and previous results from other studies showing that structural modifications in the steroid D ring/side chain region produce similar effects regardless of the stereochemistry of the A,B-ring fusion, we propose that either the 3alpha-hydroxyl groups of planar and nonplanar anesthetic steroids hydrogen bond to different amino acids on GABA(A) receptors or that this critical hydrogen bonding group interacts with membrane lipids instead of the receptor.

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Section: Methodsmentioning

confidence: 99%

Neurosteroid Analogues. 10. The Effect of Methyl Group Substitution at the C-6 and C-7 Positions on the GABA Modulatory and Anesthetic Actions of (3α,5α)- and (3α,5β)-3-Hydroxypregnan-20-one

et al. 2005

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“…Following Method B, 26 was obtained (24 mg, 0.045 mmol, 78% yield) as an off-white foam. 1 (27). Following Method A, 27 was obtained (28 mg, 0.050 mmol, 41.8% yield) as a white solid after purification by silica gel chromatography (AcOEt/petroleum ether = 70:30 v/v).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…The first modification considered was the conversion of the hydroxyl group of the 2-hydroxyacetyl substituent of budesonide into different functional groups such as fluoromethylketone, ester, amide, and thioester, the last one present in fluticasone furoate. As described in Scheme , the key step to obtain the fluoromethyl ketone side-chain is the conversion of the mesylate into fluoro to give intermediates 30 , then transformed into 31 , which was converted into secondary amine 32 , following the same approach as described for the synthesis of 11 . This intermediate was converted into 33 using the same reaction conditions previously described for 24 .…”

Section: Synthesismentioning

confidence: 99%

Novel Pyrrolidine Derivatives of Budesonide as Long Acting Inhaled Corticosteroids for the Treatment of Pulmonary Inflammatory Diseases

et al. 2018

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Inhaled corticosteroids (ICSs) represent the first line therapy for the treatment of asthma and are also extensively utilized in chronic obstructive pulmonary disease. Our goal was to develop a new ICS with a basic group, which can allow solid state feature modulation, achieving at the same time high local anti-inflammatory effect and low systemic exposure. Through a rational drug design approach, a new series of pyrrolidine derivatives of budesonide was identified. Within the series, several compounds showed nanomolar binding affinity ( K) with GR that mostly correlated with the effect in inducing GR nuclear translocation in CHO cells and anti-inflammatory effects in macrophagic cell lines. Binding and functional cell-based assays allowed identifying compound 17 as a potent ICS agonist with a PK profile showing an adequate lung retention and low systemic exposure in vivo. Finally, compound 17 proved to be more potent than budesonide in a rat model of acute pulmonary inflammation.

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“…Alcohols and phenols are converted not only into half-esters such as hemisuccinates, hemiglutarates, hemiphtalates [28], and meta-benzenesulfonates [29] but also into phosphates or even sulfates ( Figure 30.6). Alcohols and phenols are converted not only into half-esters such as hemisuccinates, hemiglutarates, hemiphtalates [28], and meta-benzenesulfonates [29] but also into phosphates or even sulfates ( Figure 30.6).…”

Section: Acylation Of Oh and Nh Functions With Acidic Chainsmentioning

confidence: 99%

Preparation of Water-Soluble Compounds by Covalent Attachment of Solubilizing Moieties

Wermuth¹,

Lesuisse²

2015

The Practice of Medicinal Chemistry

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Action of Some Steroids on the Central Nervous System of the Mouse. I. Synthetic Methods

Cited by 14 publications

References 1 publication

Neurosteroid Analogues. 10. The Effect of Methyl Group Substitution at the C-6 and C-7 Positions on the GABA Modulatory and Anesthetic Actions of (3α,5α)- and (3α,5β)-3-Hydroxypregnan-20-one

Neurosteroid Analogues. 10. The Effect of Methyl Group Substitution at the C-6 and C-7 Positions on the GABA Modulatory and Anesthetic Actions of (3α,5α)- and (3α,5β)-3-Hydroxypregnan-20-one

Novel Pyrrolidine Derivatives of Budesonide as Long Acting Inhaled Corticosteroids for the Treatment of Pulmonary Inflammatory Diseases

Preparation of Water-Soluble Compounds by Covalent Attachment of Solubilizing Moieties

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