Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3<i>S</i>)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)

Scott, James S.; Bowker, Suzanne S.; deSchoolmeester, Joanne; Gerhardt, S.; Hargreaves, David; Kilgour, Elaine; Lloyd, Adele; Mayers, Rachel M.; McCoull, William; Newcombe, Nicholas J.; Ogg, D.; Packer, Martin J.; Rees, Amanda; Revill, John; Schofield, Paul N.; Selmi, Nidhal; Swales, John G.; Whittamore, Paul R.O.

doi:10.1021/jm300592r

Cited by 53 publications

(48 citation statements)

References 35 publications

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“…The results of the presented study are in line with a similar type of study investigating the impact of another selective and potent oral 11βHSD1 inhibitor AZD4017 on IOP ( table 1 ). 15 16 However, AZD4017 was administered for a duration of 4 weeks, suggesting that a longer treatment duration in the present study may also not have provided a larger effect on IOP.…”

Section: Intraocular Pressurementioning

confidence: 78%

Oral administration of the 11β-hydroxysteroid-dehydrogenase type 1 inhibitor RO5093151 to patients with glaucoma: an adaptive, randomised, placebo-controlled clinical study

et al. 2017

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Background/aimsCortisol is involved in the regulation of intraocular pressure (IOP). This study aimed to assess the effect of 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1) inhibition by oral administration of RO5093151 on IOP.MethodsThe exposure of key ocular compartments following oral administration was assessed in rabbits. An adaptive, randomised, placebo-controlled study gated by a Bayesian decision criterion was performed in 35 patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT). Following a 7-day placebo-controlled run-in period, 200 mg twice daily RO5093151 or placebo (4:1) were administered for 7 days. The extent of 11βHSD1 inhibition was assessed by the ratio of urinary tetrahydrocortisol (5α and 5β)/tetrahydrocortisone (THF/THE). Time-matched IOP assessments were performed.ResultsA high distribution of RO5093151 into the rabbit eye was observed. In humans, a high and sustained inhibition of 11βHSD1 was shown by the decrease of THF/THE from 0.9 at baseline to 0.18 on day 7. There was no statistically significant difference in change of IOP from baseline. In the ‘worse eye’, the adjusted least square mean change from baseline was −2.7 mm Hg (95% CI −4.2 to –1.2) and −2.9(95% CI −5.9 to 0.1) in the RO5093151 and placebo group, respectively.ConclusionsDespite high inhibition of 11βHSD1 and expected moderate to high tissue distribution in ocular tissues, a 7-day treatment with a high oral dose of RO5093151 did not result in a clinically meaningful effect on IOP in patients with POAG or OHT.

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Section: Intraocular Pressurementioning

confidence: 78%

Oral administration of the 11β-hydroxysteroid-dehydrogenase type 1 inhibitor RO5093151 to patients with glaucoma: an adaptive, randomised, placebo-controlled clinical study

et al. 2017

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“…Several drugs target important enzymes like 11βhydroxysteroid dehydrogenase type-1 (11β-HSD1) [140][141][142][143][144][145][146][147][148] and protein tyrosine phosphatase-1B (PTP1B) [149]. 11β-HSD1 reduces cortisone to the active hormone cortisol, which activates glucocorticoid receptors.…”

Section: Drugs That Modulate Lipid Metabolic Pathwaysmentioning

confidence: 99%

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

2021

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The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium–glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance. Graphical abstract

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“…Heating of compounds 2 ‐R (R=H, F) with 3‐( N , N ‐dimethylamino)phenol ( 3 ) was performed in the presence of air oxygen, in order to provide oxidation of the intermediate leuco‐forms (the structures not shown) to dyes 4‐ R. We tried various solvents (propionic acid, toluene, trifluoroethanol; with and without acidic catalysts), but only in dichlorobenzene rhodamines 4 ‐R were formed in moderate yield. Careful addition of thioglycolic acid to the solutions of compounds 4 ‐R in DMF at room temperature resulted in selective substitution of the chlorine between the carboxylic acid group and the nitrogen atom [12] and resulted in the new fluorescent dyes 5 ‐R bearing a short linker and the second carboxylate. The NMR spectra of rhodamines 4 ‐R and 5 ‐R displayed broad signals at +25 °C; probably due to protonation of the pyridine nitrogen.…”

Section: Resultsmentioning

confidence: 99%

Rhodamines with a Chloronicotinic Acid Fragment for Live Cell Superresolution STED Microscopy**

Grimm¹,

Rehman²,

Stoldt

et al. 2021

Chemistry A European J

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Formylation of 2,6‐dichloro‐5‐R‐nicotinic acids at C‐4 followed by condensation with 3‐hydroxy‐N,N‐dimethylaniline gave analogs of the popular TAMRA fluorescent dye with a 2,6‐dichloro‐5‐R‐nicotinic acid residues (R=H, F). The following reaction with thioglycolic acid is selective, involves only one chlorine atom at the carbon between pyridine nitrogen and the carboxylic acid group and affords new rhodamine dyes absorbing at 564/ 573 nm and emitting at 584/ 597 nm (R=H/ F, in aq. PBS). Conjugates of the dyes with “small molecules” provided specific labeling (covalent and non‐covalent) of organelles as well as of components of the cytoskeleton in living cells and were combined with fluorescent probes prepared from 610CP and SiR dyes and applied in two‐color STED microscopy with a 775 nm STED laser.

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Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3S)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)

Cited by 53 publications

References 35 publications

Oral administration of the 11β-hydroxysteroid-dehydrogenase type 1 inhibitor RO5093151 to patients with glaucoma: an adaptive, randomised, placebo-controlled clinical study

Oral administration of the 11β-hydroxysteroid-dehydrogenase type 1 inhibitor RO5093151 to patients with glaucoma: an adaptive, randomised, placebo-controlled clinical study

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

Rhodamines with a Chloronicotinic Acid Fragment for Live Cell Superresolution STED Microscopy**

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