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Gary H Posner - One of the best experts on this subject based on the ideXlab platform.
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low calcemic highly antiproliferative 23 oxa ether analogs of the Natural Hormone 1 alpha 25 dihydroxyvitamin d3 design synthesis and preliminary biological evaluation
Journal of Medicinal Chemistry, 2007Co-Authors: Kimberly S Petersen, Patrick Dolan, Thomas W Kensler, Sara Peleg, Gary H PosnerAbstract:Eight new side-chain allylic, benzylic, and propargylic ether analogs of the Natural Hormone calcitriol have been rationally designed and easily synthesized. Three of these 23-oxa ether analogs lacking the typical side-chain OH group are more antiproliferative in vitro and desirably less calcemic in vivo than the Natural Hormone. One of these three 23-oxa analogs has transcriptional potency almost as high as that of calcitriol, even though it binds to the human vitamin D receptor only about 1% as well as calcitriol.
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difluoromethyl analogs of the Natural Hormone 1α 25 dihydroxyvitamin d3 design synthesis and preliminary biological evaluation
The Journal of Steroid Biochemistry and Molecular Biology, 2007Co-Authors: Gary H Posner, Kimberly S Petersen, Patrick Dolan, Thomas W Kensler, Byung Chul Suh, Elin S Agoston, John T Koh, Sara PelegAbstract:Abstract Three new Vitamin D analogs 3 – 5 incorporating a –CHF 2 group as an –OH surrogate have been prepared. Two of these new analogs ( 3 and 5 ) are strongly antiproliferative toward murine keratinocytes and are approximately 50 times less calciuric in vivo than the Natural Hormone calcitriol. The transcriptional activity of the 25-CHF 2 analog 3 is higher than that of the 1-CHF 2 analog 4 .
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low calcemic highly antiproliferative 1 difluoromethyl hybrid analogs of the Natural Hormone 1α 25 dihydroxyvitamin d3 design synthesis and preliminary biological evaluation
Journal of Medicinal Chemistry, 2006Co-Authors: Sara Peleg, Kimberly S Petersen, Patrick Dolan, Thomas W Kensler, Byung Chul Suh, Elin S Agoston, Gary H PosnerAbstract:Replacing the 1α-OH group of the Natural Hormone 1α,25-dihydroxyvitamin D3 (calcitriol) by a 1α-CHF2 group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo.
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a ring hydroxymethyl 19 nor analogs of the Natural Hormone 1α 25 dihydroxyvitamin d3 synthesis and preliminary biological evaluation
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Mark A Hatcher, Patrick Dolan, Thomas W Kensler, Sara Peleg, Amy A Sarjeant, Gary H PosnerAbstract:Abstract A series 5–8 of 1- and 3-CH2OH 19-nor analogs of the Hormone calcitriol (1) has been prepared. Surprisingly, 19-nor 1α-CH2OH analog 5a is more antiproliferative at 100 nM concentration than the corresponding regioisomeric analog 6a with the Natural 1α-OH group, and 1α-CH2OH hybrid analog 7a is similar in antiproliferative potency to calcitriol (1) even at low nanomolar concentrations.
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2 2 disubstituted analogues of the Natural Hormone 1α 25 dihydroxyvitamin d3 chemistry and biology
Bioorganic & Medicinal Chemistry, 2002Co-Authors: Gary H Posner, Patrick Dolan, Sara Peleg, Benjamin T Woodard, Kenneth R Crawford, Alex J Brown, Thomas W KenslerAbstract:Six new 2,2-disubstituted analogues of the Natural Hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels-Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues. Analogues 7a and are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2-3 times more active transcriptionally than calcitriol, whereas dimethylated analogue is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue is considerably less calcemic than calcitriol. Dimethylated analogue strongly suppresses parathyroid Hormone (PTH) secretion.
Sara Peleg - One of the best experts on this subject based on the ideXlab platform.
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low calcemic highly antiproliferative 23 oxa ether analogs of the Natural Hormone 1 alpha 25 dihydroxyvitamin d3 design synthesis and preliminary biological evaluation
Journal of Medicinal Chemistry, 2007Co-Authors: Kimberly S Petersen, Patrick Dolan, Thomas W Kensler, Sara Peleg, Gary H PosnerAbstract:Eight new side-chain allylic, benzylic, and propargylic ether analogs of the Natural Hormone calcitriol have been rationally designed and easily synthesized. Three of these 23-oxa ether analogs lacking the typical side-chain OH group are more antiproliferative in vitro and desirably less calcemic in vivo than the Natural Hormone. One of these three 23-oxa analogs has transcriptional potency almost as high as that of calcitriol, even though it binds to the human vitamin D receptor only about 1% as well as calcitriol.
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difluoromethyl analogs of the Natural Hormone 1α 25 dihydroxyvitamin d3 design synthesis and preliminary biological evaluation
The Journal of Steroid Biochemistry and Molecular Biology, 2007Co-Authors: Gary H Posner, Kimberly S Petersen, Patrick Dolan, Thomas W Kensler, Byung Chul Suh, Elin S Agoston, John T Koh, Sara PelegAbstract:Abstract Three new Vitamin D analogs 3 – 5 incorporating a –CHF 2 group as an –OH surrogate have been prepared. Two of these new analogs ( 3 and 5 ) are strongly antiproliferative toward murine keratinocytes and are approximately 50 times less calciuric in vivo than the Natural Hormone calcitriol. The transcriptional activity of the 25-CHF 2 analog 3 is higher than that of the 1-CHF 2 analog 4 .
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low calcemic highly antiproliferative 1 difluoromethyl hybrid analogs of the Natural Hormone 1α 25 dihydroxyvitamin d3 design synthesis and preliminary biological evaluation
Journal of Medicinal Chemistry, 2006Co-Authors: Sara Peleg, Kimberly S Petersen, Patrick Dolan, Thomas W Kensler, Byung Chul Suh, Elin S Agoston, Gary H PosnerAbstract:Replacing the 1α-OH group of the Natural Hormone 1α,25-dihydroxyvitamin D3 (calcitriol) by a 1α-CHF2 group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo.
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a ring hydroxymethyl 19 nor analogs of the Natural Hormone 1α 25 dihydroxyvitamin d3 synthesis and preliminary biological evaluation
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Mark A Hatcher, Patrick Dolan, Thomas W Kensler, Sara Peleg, Amy A Sarjeant, Gary H PosnerAbstract:Abstract A series 5–8 of 1- and 3-CH2OH 19-nor analogs of the Hormone calcitriol (1) has been prepared. Surprisingly, 19-nor 1α-CH2OH analog 5a is more antiproliferative at 100 nM concentration than the corresponding regioisomeric analog 6a with the Natural 1α-OH group, and 1α-CH2OH hybrid analog 7a is similar in antiproliferative potency to calcitriol (1) even at low nanomolar concentrations.
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2 2 disubstituted analogues of the Natural Hormone 1α 25 dihydroxyvitamin d3 chemistry and biology
Bioorganic & Medicinal Chemistry, 2002Co-Authors: Gary H Posner, Patrick Dolan, Sara Peleg, Benjamin T Woodard, Kenneth R Crawford, Alex J Brown, Thomas W KenslerAbstract:Six new 2,2-disubstituted analogues of the Natural Hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels-Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues. Analogues 7a and are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2-3 times more active transcriptionally than calcitriol, whereas dimethylated analogue is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue is considerably less calcemic than calcitriol. Dimethylated analogue strongly suppresses parathyroid Hormone (PTH) secretion.
Marco Kessler - One of the best experts on this subject based on the ideXlab platform.
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gastrointestinal pain unraveling a novel endogenous pathway through uroguanylin guanylate cyclase c cgmp activation
Pain, 2013Co-Authors: Inmaculada Silossantiago, Gerhard Hannig, Helene Eutamene, Elena E Ustinova, Sylvie G Bernier, Christopher Graul, Sarah Jacobson, Hong Jin, Elaine Liong, Marco KesslerAbstract:The Natural Hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3′,5′-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress–induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous Hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.
Marco M. Kessler - One of the best experts on this subject based on the ideXlab platform.
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Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation
PAIN, 2013Co-Authors: Inmaculada Silos-santiago, Gerhard Hannig, Helene Eutamene, Elena E Ustinova, Sylvie G Bernier, Christopher Graul, Sarah Jacobson, Hong Jin, Elaine Liong, Marco M. KesslerAbstract:The Natural Hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3',5'-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress-induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous Hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.
Karlheinrich Fritzemeier - One of the best experts on this subject based on the ideXlab platform.
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comparative analysis of the uterine and mammary gland effects of progesterone and medroxyprogesterone acetate
Maturitas, 2010Co-Authors: Christiane Otto, Iris Fuchs, Richardus Vonk, Karlheinrich FritzemeierAbstract:Abstract Objectives In combined Hormone replacement therapy (HRT) progestins are used to inhibit estradiol-activated uterine epithelial cell proliferation. In comparison to estradiol-only therapy, combined HRT leads to enhanced proliferation of mammary epithelial cells. In a quantitative mouse model, we assessed the balance between uterine and undesired mammary gland effects for two progestins that are widely used in HRT, progesterone and medroxyprogesterone acetate. Study design Mice were ovariectomized and after 14 days they were treated subcutaneously with either vehicle, estradiol (100 ng) or estradiol plus increasing doses of progesterone or medroxyprogesterone acetate for three weeks. Main outcome measures Measures for progestogenic mammary gland activity were stimulation of side-branching and stimulation of epithelial cell proliferation. Progestogenic activity in the uterus was assessed by measuring inhibition of estradiol-activated uterine epithelial cell proliferation. ED 50 and ID 50 values for the distinct readouts were obtained and dissociation factors for uterine versus mammary gland activity were calculated. Results MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, progesterone showed uterine activity at doses lower than those leading to significant stimulation of epithelial cell proliferation in the mammary gland. Conclusions Progestins do not behave the same. Use of the Natural Hormone progesterone, but not MPA, in combined Hormone therapy might offer a safety window between uterine effects and undesired proliferative activity in the mammary gland.
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comparative analysis of the uterine and mammary gland effects of drospirenone and medroxyprogesterone acetate
Endocrinology, 2008Co-Authors: Christiane Otto, Iris Fuchs, Richardus Vonk, Helga Altmann, Mario Klewer, Alexander Walter, Katja Prelle, Karlheinrich FritzemeierAbstract:The role of progestins in combined Hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women's Health Initiative study provided evidence for an increased risk of breast cancer in women treated with conjugated equine estrogens plus the synthetic progestin medroxyprogesterone acetate (MPA), compared with conjugated equine estrogens-only treatment. These findings continue to be discussed, and it remains to be clarified whether the results obtained for MPA in the Women's Health Initiative study are directly applicable to other progestins used in Hormone therapy. In this study we compared in a mouse model the effects of the synthetic progestins, MPA, and drospirenone in two major target organs: the uterus and mammary gland. As quantitative measures of progestin activity, we analyzed maintenance of pregnancy, ductal side branching in the mammary gland, and proliferation of mammary and uterine epithelial cells as well as target gene induction in both organs. The outcome of this study is that not all synthetic progestins exhibit the same effects. MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, drospirenone behaved similarly to the Natural Hormone, progesterone, and exhibited uterine activity at doses lower than those leading to considerable proliferative effects in the mammary gland. We hypothesize that the safety of combined Hormone therapy in postmenopausal women may be associated with a dissociation between the uterine and mammary gland activities of the progestin component.
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the novel progestin drospirenone and its Natural counterpart progesterone biochemical profile and antiandrogenic potential
Contraception, 1996Co-Authors: Ulrike Fuhrmann, Rolf Krattenmacher, Emily P Slater, Karlheinrich FritzemeierAbstract:Abstract Drospirenone is a novel progestin under clinical development that is similar to the Natural Hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. This specific pharmacological profile of drospirenone is defined by its pattern of binding affinities to a variety of steroid Hormone receptors. In the present study the affinity of drospirenone to the progesterone receptor (PR), the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the estrogen receptor (ER) was re-evaluated by steroid binding assays and compared to those obtained for the Natural Hormone progesterone. Drospirenone displayed high affinity to PR and MR and low binding to AR, similar to progesterone. Unlike progesterone, which showed considerable binding to GR, drospirenone exhibited only low binding to this receptor. Neither drospirenone nor progesterone did bind to the ER. In addition to receptor binding studies, transactivation assays were carried out to investigated the effects of drospirenone and progesterone on AR-, GR-, and MR-mediated induction of transcription. Both progestins showed no androgenic but antiandrogenic activity by inhibiting AR-mediated transcription in a dose-dependent manner. This observation could be confirmed by in vivo experiments carried out with orchiectomized male rats, where the antiandrogenic potency of drospirenone was found to be about five- to ten-fold higher than that of progesterone. In contrast to progesterone, drospirenone was devoid of glucocorticoid activity. Both progestins did not show any antiglucocorticoid action. Furthermore, drospirenone and progesterone both showed considerable antimineralocorticoid activity and weak mineralocorticoid activity.
