Pyrrolidine-pyrazole ureas as potent and selective inhibitors of 11β-hydroxysteroid-dehydrogenase type 1

Venier, Olivier; Pascal, Cécile; Braun, Alain; Namane, Claudie; Mougenot, Patrick; Crespin, Olivier; Pacquet, François; Mougenot, Cécile; Monseau, Catherine; Onofri, Bénédicte; Dadji-Faïhun, Rommel; Leger, Céline; Ben-Hassine, Majdi; Van-Pham, Thao; Ragot, Jean-Luc; Philippo, Christophe; Güssregen, Stefan; Engel, C.K.; Farjot, Géraldine; Noah, Lionel; Maniani, Karima; Nicolaï, Eric

doi:10.1016/j.bmcl.2011.02.111

Cited by 14 publications

(8 citation statements)

References 34 publications

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“…The chemical structure of Avirulins is distinct from other known antiretroviral drugs, making this class of compounds potentially valuable additions to the multidrug cocktails of ART. To our knowledge, no drug activity has been reported elsewhere for this class of compounds, though one group has reported unrelated activity of related pyrrolidine–pyrazole urea compounds with dehydrogenase inhibition activity [41]. Av-5, Av- 26, and Av-14 were not cytotoxic at concentrations as high as 100 µM.…”

Section: Discussionmentioning

confidence: 99%

Avirulins, a Novel Class of HIV-1 Reverse Transcriptase Inhibitors Effective in the Female Reproductive Tract Mucosa

Cherne

Hall

Kellner

et al. 2019

Viruses

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While extensive research efforts have decreased human immunodeficiency virus (HIV) transmissions and mortalities, new challenges have arisen in the fight to eradicate HIV. Drug resistance to antiretroviral therapy threatens infected individuals, while the prevalence of heterosexual transmission creates an urgent need for therapies effective in the female reproductive tract (FRT) mucosa. We screened a library of 2095 small molecule compounds comprising a unique chemical space, purchased from Asinex Corporation, for antiviral activity against human immunodeficiency virus type 1 (HIV-1) strain BaL and identified several molecular representatives of a unique class of HIV-1 inhibitors, which we termed “Avirulins.” We determined that Avirulins were active against clinical isolates of HIV-1 from genetically variant subtypes, several of which have reduced sensitivity to other antivirals. Avirulins displayed specific dose-dependent inhibition of the HIV-1 drug target, reverse transcriptase (RT). Avirulins were effective against several nucleoside RT-inhibitor resistant strains of HIV-1, as well as one nonnucleoside RT-inhibitor resistant strain containing a 106A mutation, suggesting a noncompetitive mechanism of action. Drugs, which are damaging to the FRT, can increase the risk of HIV-1 transmission. We therefore explored the cytotoxicity of Avirulins against epithelial cells derived from the FRT and found no significant toxicity, even at the highest concentrations tested. Importantly, Avirulin antiviral activity was not diminished in human cervico–vaginal fluid, suggesting retained potency in the milieu of the FRT. Based on these promising results, Avirulins should be valuable chemical scaffolds for development into next-generation treatments and preventatives that target HIV-1.

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Section: Discussionmentioning

confidence: 99%

Avirulins, a Novel Class of HIV-1 Reverse Transcriptase Inhibitors Effective in the Female Reproductive Tract Mucosa

Cherne

Hall

Kellner

et al. 2019

Viruses

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show abstract

“…Other companies, including Novartis, 116 Merck-Serono, 117,118 Sanofi-Aventis, 119 Schering-Plough 120 and in particular Abbott, [121][122][123][124][125][126][127][128] have also published work in this area but have not, to the best of our knowledge, progressed candidates to the clinic.…”

Section: Other Companies and Institutionsmentioning

confidence: 98%

Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

Scott¹,

Chooramun²

2012

Drug Discovery

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“…As shown in Figure 1, the long chain motif of rosiglitazone has been kept with the changed 4-formamide- N -methylpiperidine or 4-hydroxy- N -ethanonepiperidine bridges between two benzene rings, and then guanidine was introduced to the par a-position of ring B where a substituted thiazolidine was originally. Furthermore, as guanidine’s isosteric urea core has also shown capacity in decreasing liver TG [29], this encouraged us to try to replace guanidine with (thio)urea moieties. As a result compound 7i was discovered to be a good leptin regulator and to improve hepatic steatosis symptoms in DIO mice.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Urea- and Guanidine-Based Derivatives for the Treatment of Obesity-Related Hepatic Steatosis

Liang

Pei

et al. 2014

Molecules

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Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thio)urea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethyl)ureido)benzyl)piperidin-4-yl)-3-(trifluoromethyl) benzamide (7i) was found to be a potent regulator of leptin expression in 3T3-L1 adipocytes. Treatment with 7i at a dose of 50 mg/kg/day for 35 days reduced the body weight and liver weight of diet-induced obesity mice by 13.5% and 18.4%, respectively, while also improving the serum levels of triglyceride, total cholesterol, leptin, adiponectin, LDL-c, HDL-c. Hematoxylin-eosin (H&E) and Oil Red O staining also confirmed that 7i ameliorated fat deposition in liver tissue and restricted the size of adipocytes in obesity-related fatty liver disease.

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Pyrrolidine-pyrazole ureas as potent and selective inhibitors of 11β-hydroxysteroid-dehydrogenase type 1

Cited by 14 publications

References 34 publications

Avirulins, a Novel Class of HIV-1 Reverse Transcriptase Inhibitors Effective in the Female Reproductive Tract Mucosa

Avirulins, a Novel Class of HIV-1 Reverse Transcriptase Inhibitors Effective in the Female Reproductive Tract Mucosa

Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

Synthesis and Biological Evaluation of Novel Urea- and Guanidine-Based Derivatives for the Treatment of Obesity-Related Hepatic Steatosis

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