The Experts below are selected from a list of 42 Experts worldwide ranked by ideXlab platform

Joseph S Tash - One of the best experts on this subject based on the ideXlab platform.

  • the orally active Male Contraceptive Agent h2 gamendazole interacts with organic anion transporting polypeptides expressed in human hepatocytes 1064 18
    The FASEB Journal, 2014
    Co-Authors: Jessica Shoop, Joseph S Tash, Sudhakar Jakkaraj, Gunda I. Georg, Lesya M Holets, Colleen A Flynn, Michael Baltezor, Bruno Hagenbuch
    Abstract:

    The non-hormonal Male Contraceptive H2-gamendazole (H2-GMZ) is a lonidamine derivative that has been shown to accumulate in rat testes at levels about 10 times higher than in the liver and other or...

  • a novel potent indazole carboxylic acid derivative blocks spermatogenesis and is Contraceptive in rats after a single oral dose
    Biology of Reproduction, 2008
    Co-Authors: Joseph S Tash, Sheri Ann Hild, Ramappa Chakrasali, Sudhakar Jakkaraj, Barbara J. Attardi, Gunda I. Georg
    Abstract:

    : Women have historically been the focus for development of new Contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal Male Contraceptive Agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile Male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal Male Contraceptive Agent can occur.

  • gamendazole an orally active indazole carboxylic acid Male Contraceptive Agent targets hsp90ab1 hsp90beta and eef1a1 eef1a and stimulates il1a transcription in rat sertoli cells
    Biology of Reproduction, 2008
    Co-Authors: Joseph S Tash, Ramappa Chakrasali, Sudhakar Jakkaraj, Jennifer R Hughes, Kendall S Smith, Kaori I Hornbaker, Leslie L Heckert, Sedide B Ozturk, Kyle M Hadden, Terri Goss Kinzy
    Abstract:

    Gamendazole was recently identified as an orally active antispermatogenic compound with antifertility effects. The cellular mechanism(s) through which these effects occur and the molecular target(s) of gamendazole action are currently unknown. Gamendazole was recently designed as a potent orally active antispermatogenic Male Contraceptive Agent. Here, we report the identification of binding targets and propose a testable mechanism of action for this antispermatogenic Agent. Both HSP90AB1 (previously known as HSP90beta [heat shock 90-kDa protein 1, beta]) and EEF1A1 (previously known as eEF1A [eukaryotic translation elongation factor 1 alpha 1]) were identified as binding targets by biotinylated gamendazole (BT-GMZ) affinity purification from testis, Sertoli cells, and ID8 ovarian cancer cells; identification was confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and Western blot analysis. BT-GMZ bound to purified yeast HSP82 (homologue to mammalian HSP90AB1) and EEF1A1, but not to TEF3 or HBS1, and was competed by unlabeled gamendazole. However, gamendazole did not inhibit nucleotide binding by EEF1A1. Gamendazole binding to purified Saccharomyces cerevisiae HSP82 inhibited luciferase refolding and was not competed by the HSP90 drugs geldanamycin or novobiocin analogue, KU-1. Gamendazole elicited degradation of the HSP90-dependent client proteins AKT1 and ERBB2 and had an antiproliferative effect in MCF-7 cells without inducing HSP90. These data suggest that gamendazole may represent a new class of selective HSP90AB1 and EEF1A1 inhibitors. Testis gene microarray analysis from gamendazole-treated rats showed a marked, rapid increase in three interleukin 1 genes and Nfkbia (NF-kappaB inhibitor alpha) 4 h after oral administration. A spike in II1a transcription was confirmed by RT-PCR in primary Sertoli cells 60 min after exposure to 100 nM gamendazole, demonstrating that Sertoli cells are a target. AKT1, NFKB, and interleukin 1 are known regulators of the Sertoli cell-spermatid junctional complexes. A current model for gamendazole action posits that this pathway links interaction with HSP90AB1 and EEF1A1 to the loss of spermatids and resulting infertility.

Gunda I. Georg - One of the best experts on this subject based on the ideXlab platform.

  • the orally active Male Contraceptive Agent h2 gamendazole interacts with organic anion transporting polypeptides expressed in human hepatocytes 1064 18
    The FASEB Journal, 2014
    Co-Authors: Jessica Shoop, Joseph S Tash, Sudhakar Jakkaraj, Gunda I. Georg, Lesya M Holets, Colleen A Flynn, Michael Baltezor, Bruno Hagenbuch
    Abstract:

    The non-hormonal Male Contraceptive H2-gamendazole (H2-GMZ) is a lonidamine derivative that has been shown to accumulate in rat testes at levels about 10 times higher than in the liver and other or...

  • a novel potent indazole carboxylic acid derivative blocks spermatogenesis and is Contraceptive in rats after a single oral dose
    Biology of Reproduction, 2008
    Co-Authors: Joseph S Tash, Sheri Ann Hild, Ramappa Chakrasali, Sudhakar Jakkaraj, Barbara J. Attardi, Gunda I. Georg
    Abstract:

    : Women have historically been the focus for development of new Contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal Male Contraceptive Agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile Male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal Male Contraceptive Agent can occur.

Smritinath Chakraborty - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and assessment of fertility regulating potential of 2 2 chloroacetamidobenzyl 3 3 indolyl quinoline in adult rats as a Male Contraceptive Agent
    Contraception, 2008
    Co-Authors: Sujit K Bhowal, Sanchita Lala, Abhijit Hazra, Priyankar Paira, Sukdeb Banerjee, Nirup B Mondal, Smritinath Chakraborty
    Abstract:

    Abstract Background The purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2″-chloroacetamidobenzyl)-3-(3′-indolyl) quinoline in Male rats. Study Design Rats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured. Results Functional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment. Conclusion The results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as Male Contraceptive Agent.

  • original research article synthesis and assessment of fertility regulating potential of 2 2 chloroacetamidobenzyl 3 3 indolyl quinoline in adult rats as a Male Contraceptive Agent
    2008
    Co-Authors: Sujit K Bhowal, Sanchita Lala, Abhijit Hazra, Priyankar Paira, Sukdeb Banerjee, Nirup B Mondal, Smritinath Chakraborty
    Abstract:

    Background: The purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2″-chloroacetamidobenzyl)3-(3′-indolyl) quinoline in Male rats. Study Design: Rats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured. Results: Functional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment. Conclusion: The results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as Male Contraceptive Agent.

Sudhakar Jakkaraj - One of the best experts on this subject based on the ideXlab platform.

  • the orally active Male Contraceptive Agent h2 gamendazole interacts with organic anion transporting polypeptides expressed in human hepatocytes 1064 18
    The FASEB Journal, 2014
    Co-Authors: Jessica Shoop, Joseph S Tash, Sudhakar Jakkaraj, Gunda I. Georg, Lesya M Holets, Colleen A Flynn, Michael Baltezor, Bruno Hagenbuch
    Abstract:

    The non-hormonal Male Contraceptive H2-gamendazole (H2-GMZ) is a lonidamine derivative that has been shown to accumulate in rat testes at levels about 10 times higher than in the liver and other or...

  • a novel potent indazole carboxylic acid derivative blocks spermatogenesis and is Contraceptive in rats after a single oral dose
    Biology of Reproduction, 2008
    Co-Authors: Joseph S Tash, Sheri Ann Hild, Ramappa Chakrasali, Sudhakar Jakkaraj, Barbara J. Attardi, Gunda I. Georg
    Abstract:

    : Women have historically been the focus for development of new Contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal Male Contraceptive Agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile Male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal Male Contraceptive Agent can occur.

  • gamendazole an orally active indazole carboxylic acid Male Contraceptive Agent targets hsp90ab1 hsp90beta and eef1a1 eef1a and stimulates il1a transcription in rat sertoli cells
    Biology of Reproduction, 2008
    Co-Authors: Joseph S Tash, Ramappa Chakrasali, Sudhakar Jakkaraj, Jennifer R Hughes, Kendall S Smith, Kaori I Hornbaker, Leslie L Heckert, Sedide B Ozturk, Kyle M Hadden, Terri Goss Kinzy
    Abstract:

    Gamendazole was recently identified as an orally active antispermatogenic compound with antifertility effects. The cellular mechanism(s) through which these effects occur and the molecular target(s) of gamendazole action are currently unknown. Gamendazole was recently designed as a potent orally active antispermatogenic Male Contraceptive Agent. Here, we report the identification of binding targets and propose a testable mechanism of action for this antispermatogenic Agent. Both HSP90AB1 (previously known as HSP90beta [heat shock 90-kDa protein 1, beta]) and EEF1A1 (previously known as eEF1A [eukaryotic translation elongation factor 1 alpha 1]) were identified as binding targets by biotinylated gamendazole (BT-GMZ) affinity purification from testis, Sertoli cells, and ID8 ovarian cancer cells; identification was confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and Western blot analysis. BT-GMZ bound to purified yeast HSP82 (homologue to mammalian HSP90AB1) and EEF1A1, but not to TEF3 or HBS1, and was competed by unlabeled gamendazole. However, gamendazole did not inhibit nucleotide binding by EEF1A1. Gamendazole binding to purified Saccharomyces cerevisiae HSP82 inhibited luciferase refolding and was not competed by the HSP90 drugs geldanamycin or novobiocin analogue, KU-1. Gamendazole elicited degradation of the HSP90-dependent client proteins AKT1 and ERBB2 and had an antiproliferative effect in MCF-7 cells without inducing HSP90. These data suggest that gamendazole may represent a new class of selective HSP90AB1 and EEF1A1 inhibitors. Testis gene microarray analysis from gamendazole-treated rats showed a marked, rapid increase in three interleukin 1 genes and Nfkbia (NF-kappaB inhibitor alpha) 4 h after oral administration. A spike in II1a transcription was confirmed by RT-PCR in primary Sertoli cells 60 min after exposure to 100 nM gamendazole, demonstrating that Sertoli cells are a target. AKT1, NFKB, and interleukin 1 are known regulators of the Sertoli cell-spermatid junctional complexes. A current model for gamendazole action posits that this pathway links interaction with HSP90AB1 and EEF1A1 to the loss of spermatids and resulting infertility.

Sujit K Bhowal - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and assessment of fertility regulating potential of 2 2 chloroacetamidobenzyl 3 3 indolyl quinoline in adult rats as a Male Contraceptive Agent
    Contraception, 2008
    Co-Authors: Sujit K Bhowal, Sanchita Lala, Abhijit Hazra, Priyankar Paira, Sukdeb Banerjee, Nirup B Mondal, Smritinath Chakraborty
    Abstract:

    Abstract Background The purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2″-chloroacetamidobenzyl)-3-(3′-indolyl) quinoline in Male rats. Study Design Rats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured. Results Functional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment. Conclusion The results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as Male Contraceptive Agent.

  • original research article synthesis and assessment of fertility regulating potential of 2 2 chloroacetamidobenzyl 3 3 indolyl quinoline in adult rats as a Male Contraceptive Agent
    2008
    Co-Authors: Sujit K Bhowal, Sanchita Lala, Abhijit Hazra, Priyankar Paira, Sukdeb Banerjee, Nirup B Mondal, Smritinath Chakraborty
    Abstract:

    Background: The purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2″-chloroacetamidobenzyl)3-(3′-indolyl) quinoline in Male rats. Study Design: Rats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured. Results: Functional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment. Conclusion: The results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as Male Contraceptive Agent.