Endocrinology and Nephrology Unit

Québec, Canada

Endocrinology and Nephrology Unit

Québec, Canada
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Cortes-Benitez F.,Endocrinology and Nephrology Unit | Cortes-Benitez F.,National Autonomous University of Mexico | Roy J.,Endocrinology and Nephrology Unit | Roy J.,Laval University | And 4 more authors.
Bioorganic and Medicinal Chemistry | Year: 2017

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a major player in human endocrinology, being one of the most important enzymes involved in testosterone production. To capitalize on the discovery of RM-532-105, a steroidal 17β-HSD3 inhibitor, we explored the effect of its backbone configuration on inhibitory activity, androgenic profile, and metabolic stability. Two modifications that greatly alter the natural shape of steroids, i.e. inversion of the methyl on carbon 13 (13α-CH3 instead of 13β-CH3) and inversion of the hydrogen on carbon 5 (5β-H instead of 5α-H), were tested after the syntheses in 6 steps of 2 isomeric forms (5α/13α-RM-532-105 (6a) and 5β/13β-RM-532-105 (6b), respectively) of the 17β-HSD3 inhibitor RM-532-105 (5α/13β-configurations). For compound 6b, a cis/trans junction of the A/B rings did not significantly alter the inhibitory activity on 17β-HSD3 (IC50 = 0.15 μM) as well as the liver microsomal stability (16.6% of 6b remaining after 1 h incubation) compared to RM-532-105 (IC50 = 0.11 μM and 14.1% remaining). In contrast, a trans/cis junction of C/D rings reduced the inhibitory activity on 17β-HSD3 (IC50 = 1.09 μM) but increased the metabolic stability with 29.4% of compound 6a remaining after incubation. The structural modifications represented by compounds 6a and 6b did not change the non-androgenicity profile of an androsterone derivative such as RM-532-105, but slightly increased its cytotoxic activity. © 2017 Elsevier Ltd


Trottier A.,Endocrinology and Nephrology Unit | Maltais R.,Endocrinology and Nephrology Unit | Ayan D.,Endocrinology and Nephrology Unit | Barbeau X.,Laval University | And 6 more authors.
Biochemical Pharmacology | Year: 2017

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the biosynthesis of estradiol, the major bioactive endogenous estrogen in mammals, and constitutes an interesting therapeutic target for estrogen-dependent diseases. A steroidal derivative, 3-([(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl) benzamide (PBRM), has recently been described as a non-estrogenic, irreversible inhibitor of 17β-HSD1. However, the mode of action of this inhibitor and its selectivity profile have not yet been elucidated. We assessed PBRM potency via in vitro kinetic measurements. The mechanism of enzyme inactivation was also investigated using interspecies (human, mouse, pig and monkey) comparisons via both in vitro assays and in silico analysis. Mouse and human plasma protein binding of PBRM was determined, whereas its selectivity of action was studied using a wide range of potential off-targets (e.g. GPCR, hERG, CYPs, etc.). The affinity constant (K i =368nM) and the enzyme inactivation rate (k inact =0.087min-1) values for PBRM were determined with purified 17β-HSD1. PBRM was found to be covalently linked to the enzyme. A long delay period (i.e. 3-5days) is required to recover 17β-HSD1 activity following a pretreatment of breast and placenta cell lines with PBRM. Mechanistic analyses showed important interspecies differences of 17β-HSD1 inhibition which support the importance of inactivation for PBRM effect. Evidences of the potency and selectivity of action presented herein for this first non-estrogenic and steroidal covalent irreversible inhibitor of 17β-HSD1 warrant its further development as a potential drug candidate for estrogen-dependent disorders. © 2017 Elsevier Inc.


Dutour R.,Endocrinology and Nephrology Unit | Dutour R.,Laval University | Poirier D.,Endocrinology and Nephrology Unit | Poirier D.,Laval University
European Journal of Medicinal Chemistry | Year: 2017

Human cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of various drugs. This enzyme catalyzes the hydroxylation of aryl compounds, thus generating more polar metabolites that can be easily excreted. CYP1B1 is also known for its ability to activate procarcinogens into carcinogens. For example, it can hydroxylate 17β-estradiol (E2) into 4-hydroxy-E2, which can promote tumorigenesis as a potent estrogen, or after being transformed into E2-3,4-quinone. Since elevated expression levels of CYP1B1 have been reported in various cancers, but not in normal tissues, this enzyme represents an interesting therapeutic target. This review put emphasis on different families of inhibitors, especially those reported since 2003. © 2017 Elsevier Masson SAS


PubMed | Endocrinology and Nephrology Unit, Institute National Of Sante Publique Du Quebec and Laval University
Type: | Journal: BMJ (Clinical research ed.) | Year: 2016

To investigate whether bariatric surgery increases the risk of fracture.Retrospective nested case-control study.Patients who underwent bariatric surgery in the province of Quebec, Canada, between 2001 and 2014, selected using healthcare administrative databases.12676 patients who underwent bariatric surgery, age and sex matched with 38028 obese and 126760 non-obese controls.Incidence and sites of fracture in patients who had undergone bariatric surgery compared with obese and non-obese controls. Fracture risk was also compared before and after surgery (index date) within each group and by type of surgery from 2006 to 2014. Multivariate conditional Poisson regression models were adjusted for fracture history, number of comorbidities, sociomaterial deprivation, and area of residence.Before surgery, patients undergoing bariatric surgery (9169 (72.3%) women; mean age 42 (SD 11) years) were more likely to fracture (1326; 10.5%) than were obese (3065; 8.1%) or non-obese (8329; 6.6%) controls. A mean of 4.4 years after surgery, bariatric patients were more susceptible to fracture (514; 4.1%) than were obese (1013; 2.7%) and non-obese (3008; 2.4%) controls. Postoperative adjusted fracture risk was higher in the bariatric group than in the obese (relative risk 1.38, 95% confidence interval 1.23 to 1.55) and non-obese (1.44, 1.29 to 1.59) groups. Before surgery, the risk of distal lower limb fracture was higher, upper limb fracture risk was lower, and risk of clinical spine, hip, femur, or pelvic fractures was similar in the bariatric and obese groups compared with the non-obese group. After surgery, risk of distal lower limb fracture decreased (relative risk 0.66, 0.56 to 0.78), whereas risk of upper limb (1.64, 1.40 to 1.93), clinical spine (1.78, 1.08 to 2.93), pelvic, hip, or femur (2.52, 1.78 to 3.59) fractures increased. The increase in risk of fracture reached significance only for biliopancreatic diversion.Patients undergoing bariatric surgery were more likely to have fractures than were obese or non-obese controls, and this risk remained higher after surgery. Fracture risk was site specific, changing from a pattern associated with obesity to a pattern typical of osteoporosis after surgery. Only biliopancreatic diversion was clearly associated with fracture risk; however, results for Roux-en-Y gastric bypass and sleeve gastrectomy remain inconclusive. Fracture risk assessment and management should be part of bariatric care.


Ouellet C.,Endocrinology and Nephrology Unit | Ouellet C.,Laval University | Ouellet E.,Endocrinology and Nephrology Unit | Ouellet E.,Laval University | And 2 more authors.
Investigational New Drugs | Year: 2015

Selective estrogen receptor modulators (SERMs) are currently in use in the hormonal therapy of breast cancer. In that respect, a new hormone-related approach is the therapeutical inhibition of steroid sulfatase (STS), which converts inactive, sulfated steroids into active hormones. We investigated the potential of 6-EO-14, a non-steroidal STS inhibitor with SERM potential. The latter compound, which exhibits a sulfamate moiety, releases the phenol derivative 8-EO-14 after the irreversible inhibition of STS. STS was inhibited by 6-EO-14 (IC50=0.3 μM), but not 8-EO-14, in HEK-293 cells transfected with an STS expression vector. The SERM potential of 8-EO-14 was assessed in osteoblast-like Saos-2 cells by investigating its effect on cell proliferation and on the activity of alkaline phosphatase (ALP), a specific differentiation marker. Saos-2 cell proliferation was increased by 21 % following 8-EO-14 addition (1 μM), and 8-EO-14 induced ALP activity (31 % increase at 0.1 nM) via estrogen receptor alpha (ERα) similarly to the SERM raloxifene. As compared to estradiol (E2) (100 %), the relative binding affinity of 6-EO-14 and 8-EO-14) for ERα was found to be weak (0.09 and 0.01 %, respectively). When assessed in two estrogen-dependent human breast cancer cell lines (MCF-7 and T-47D), 8-EO-14 did not support MCF-7 cell proliferation, whereas both 8-EO-14 and 6-EO-14 exhibited estrogen-like growth stimulation in T-47D cells. These two compounds were also unable to block E2-induced cell proliferation, suggesting their lack of antiestrogenic activity. Despite the known potency of 6-EO-14 as an STS inhibitor, the observed trophic activity of this new scaffold towards ERα-positive cells needs to be carefully considered prior to its potential utilization as a therapeutic agent. © 2014 Springer Science+Business Media New York.


Perreault M.,Endocrinology and Nephrology Unit | Maltais R.,Endocrinology and Nephrology Unit | Dutour R.,Endocrinology and Nephrology Unit | Poirier D.,Endocrinology and Nephrology Unit | Poirier D.,Laval University
Steroids | Year: 2016

RM-133 is a key representative of a new family of aminosteroids reported as potent anticancer agents. Although RM-133 produced interesting results in 4 mouse xenograft cancer models when injected subcutaneously, it needs to be improved to increase its in vivo potency. Thus, to obtain an analog of RM-133 with a better drug potential, a structure-activity relationship study was conducted by synthesizing eleven RM-133-related compounds and addressing their antiproliferative activity on 3 human cancer cells (HL-60, OVCAR-3 and PANC-1) and 3 human normal cell lines (primary ovary, pancreas and renal proximal tubule) as well as their metabolic stability in human liver microsomes. When the 2β-tertiary amine of RM-133 was transformed into a salt or moved to position 3β, the anticancer activity was lost. Modifying the orientation of the side chain of RM-133 increased anticancer activity and selectivity, but led to a drastic loss of stability. The protection of the 3α-hydroxyl of RM-133 by the formation of an ester or a carbamate stabilized the molecule against the phase I metabolic enzymes without affecting its anticancer activity. In comparison to RM-133, the 3-dimethylcarbamate derivative 3 is more selective for cancer cells over normal cells and is much more stable in liver microsomes. Those results support the use of a pro-drug strategy targeting the 3α-hydroxyl of RM-133 as an approach to improve its drug properties. The work presented will enable the development of an optimized anticancer drug of the aminosteroid family that is suitable for a future phase I clinical trial. © 2016 Elsevier Inc.


Murr J.,Center Dexcellence Sur Le Vieillissement Of Quebec | Murr J.,Laval University | Carmichael P.-H.,Center Dexcellence Sur Le Vieillissement Of Quebec | Julien P.,Laval University | And 3 more authors.
Neurobiology of Aging | Year: 2014

This study examines the association of plasma oxidized low-density lipoprotein (OxLDL) levels with all-cause dementia, including Alzheimer's disease (AD) and vascular dementia. Data are taken from the Canadian Study of Health and Aging, a population-based study of a representative sample of persons aged more than 65 years conducted from 1991 to 2002. The present study sample included 670 subjects of which, 155 developed all-cause dementia with 109 cases of AD and 32 of vascular dementia. In Cox regression models, no association between OxLDL and risks of dementia or subtypes was found. A triple interaction between OxLDL, sex, and history of cardiovascular disease on the risk of AD (p= 0.0077) was found. Increased levels of OxLDL were significantly associated with an increased risk of AD in men with a history of cardiovascular disease (hazard ratio= 1.11; 95% confidence interval 1.04-1.19); no association in women was found. These findings suggest that increased levels of OxLDL are not associated with the risk of dementia, AD, and vascular dementia. The association of OxLDL with AD in men with a history of cardiovascular disease merits further investigation. © 2014 Elsevier Inc.


PubMed | Endocrinology and Nephrology Unit and Laval University
Type: | Journal: Steroids | Year: 2016

RM-133 is a key representative of a new family of aminosteroids reported as potent anticancer agents. Although RM-133 produced interesting results in 4 mouse xenograft cancer models when injected subcutaneously, it needs to be improved to increase its in vivo potency. Thus, to obtain an analog of RM-133 with a better drug potential, a structure-activity relationship study was conducted by synthesizing eleven RM-133-related compounds and addressing their antiproliferative activity on 3 human cancer cells (HL-60, OVCAR-3 and PANC-1) and 3 human normal cell lines (primary ovary, pancreas and renal proximal tubule) as well as their metabolic stability in human liver microsomes. When the 2-tertiary amine of RM-133 was transformed into a salt or moved to position 3, the anticancer activity was lost. Modifying the orientation of the side chain of RM-133 increased anticancer activity and selectivity, but led to a drastic loss of stability. The protection of the 3-hydroxyl of RM-133 by the formation of an ester or a carbamate stabilized the molecule against the phase I metabolic enzymes without affecting its anticancer activity. In comparison to RM-133, the 3-dimethylcarbamate derivative 3 is more selective for cancer cells over normal cells and is much more stable in liver microsomes. Those results support the use of a pro-drug strategy targeting the 3-hydroxyl of RM-133 as an approach to improve its drug properties. The work presented will enable the development of an optimized anticancer drug of the aminosteroid family that is suitable for a future phase I clinical trial.


Anticancer structure-activity relationship studies on aminosteroid (5-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5-androstane-3,17-diol), which possesses high invitro and invivo activities against several cancer cells, and selectivity over normal cells. However, the relatively weak metabolic stability of RM-133 has been a drawback to its progression toward clinical trials. We investigated the replacement of the androstane backbone by a more stable mestranol moiety. The resulting compound, called RM-581 ({4-[17-ethynyl-17-hydroxy-3-methoxyestra-1,3,5(10)-trien-2-yl]piperazin-1-yl}[(2S)-1-(quinolin-2-ylcarbonyl)pyrrolidin-2-yl]methanone), was synthesized efficiently in only five steps from commercially available estrone. In comparison with RM-133, RM-581 was found to be twice as metabolically stable, retains potent cytotoxic activity in breast cancer MCF-7 cell culture, and fully blocks tumor growth in a mouse xenograft model of breast cancer. Advantageously, the selectivity over normal cells has been increased with this estrane version of RM-133. In fact, RM-581 showed a better selectivity index (15.3 vs. 3.0) for breast cancer MCF-7 cells over normal breast MCF-10A cells, and was found to be nontoxic toward primary human kidney proximal tubule cells at doses reaching 50m.


PubMed | Endocrinology and Nephrology Unit
Type: Journal Article | Journal: Investigational new drugs | Year: 2015

Selective estrogen receptor modulators (SERMs) are currently in use in the hormonal therapy of breast cancer. In that respect, a new hormone-related approach is the therapeutical inhibition of steroid sulfatase (STS), which converts inactive, sulfated steroids into active hormones. We investigated the potential of 6-EO-14, a non-steroidal STS inhibitor with SERM potential. The latter compound, which exhibits a sulfamate moiety, releases the phenol derivative 8-EO-14 after the irreversible inhibition of STS. STS was inhibited by 6-EO-14 (IC50=0.3 M), but not 8-EO-14, in HEK-293 cells transfected with an STS expression vector. The SERM potential of 8-EO-14 was assessed in osteoblast-like Saos-2 cells by investigating its effect on cell proliferation and on the activity of alkaline phosphatase (ALP), a specific differentiation marker. Saos-2 cell proliferation was increased by 21 % following 8-EO-14 addition (1 M), and 8-EO-14 induced ALP activity (31 % increase at 0.1 nM) via estrogen receptor alpha (ER) similarly to the SERM raloxifene. As compared to estradiol (E2) (100 %), the relative binding affinity of 6-EO-14 and 8-EO-14) for ER was found to be weak (0.09 and 0.01 %, respectively). When assessed in two estrogen-dependent human breast cancer cell lines (MCF-7 and T-47D), 8-EO-14 did not support MCF-7 cell proliferation, whereas both 8-EO-14 and 6-EO-14 exhibited estrogen-like growth stimulation in T-47D cells. These two compounds were also unable to block E2-induced cell proliferation, suggesting their lack of antiestrogenic activity. Despite the known potency of 6-EO-14 as an STS inhibitor, the observed trophic activity of this new scaffold towards ER-positive cells needs to be carefully considered prior to its potential utilization as a therapeutic agent.

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