34 results on '"Pai LY"'
Search Results
2. Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic.
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Jiang J, Ding FX, Zhou X, Bateman TJ, Dong S, Gu X, Keh deJesus R, Pio B, Tang H, Chobanian HR, Levorse D, Hu M, Thomas-Fowlkes B, Margulis M, Koehler M, Weinglass A, Gibson J, Houle K, Yudkovitz J, Hampton C, Pai LY, Samuel K, Cutarelli T, Sullivan K, Parmee ER, Davies I, and Pasternak A
- Subjects
- Action Potentials drug effects, Animals, Benzofurans chemistry, Blood Pressure drug effects, Diuretics chemistry, Diuretics metabolism, Diuretics pharmacology, Dogs, Half-Life, Haplorhini, Humans, Male, Natriuretic Agents metabolism, Natriuretic Agents pharmacology, Piperazines chemistry, Potassium urine, Potassium Channel Blockers metabolism, Potassium Channel Blockers pharmacology, Potassium Channels, Inwardly Rectifying metabolism, Rats, Rats, Inbred SHR, Natriuretic Agents chemistry, Potassium Channel Blockers chemistry, Potassium Channels, Inwardly Rectifying antagonists & inhibitors
- Abstract
A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.
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- 2021
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3. Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947.
- Author
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Brockunier L, Stelmach J, Guo J, Spencer T, Rosauer K, Bansal A, Cai SJ, Chen N, Cummings J, Huang L, Johnson T, Levesque S, Luo L, Maloney K, Metzger J, Mortko C, Ortega K, Pai LY, Pereira A, Salituro G, Shang J, Shepherd C, Sherrie Xu S, Yang Q, Cui J, Roy S, Parmee E, and Raghavan S
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- Antihypertensive Agents chemistry, Dose-Response Relationship, Drug, Humans, Molecular Structure, Structure-Activity Relationship, Antihypertensive Agents pharmacology, Drug Discovery, Hypertension drug therapy, Soluble Guanylyl Cyclase metabolism
- Abstract
The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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4. Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores.
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Dong S, VanGelder K, Shi ZC, Yu Y, Wu Z, Ferguson R, Guo ZZ, Tang H, Frie J, Fu Q, Gu X, Priest BT, Thomas-Fowlkes B, Weinglass A, Margulis M, Liu J, Pai LY, Hampton C, Haimbach RE, Owens K, Tong V, Xu S, Hu M, Zingaro GJ, Morissette P, Ehrhart J, Roy S, Sullivan K, and Pasternak A
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- Animals, Disease Models, Animal, Dogs, ERG1 Potassium Channel antagonists & inhibitors, Half-Life, Hypertension drug therapy, Potassium Channel Blockers pharmacokinetics, Potassium Channel Blockers therapeutic use, Potassium Channels, Inwardly Rectifying metabolism, Pyrimidines chemistry, Rats, Rats, Inbred SHR, Spiro Compounds chemistry, Structure-Activity Relationship, Thiadiazoles chemistry, ERG1 Potassium Channel metabolism, Potassium Channel Blockers chemistry, Potassium Channels, Inwardly Rectifying antagonists & inhibitors
- Abstract
SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
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- 2017
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5. The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics.
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Chobanian HR, Guo Y, Pio B, Tang H, Teumelsan N, Clements M, Frie J, Ferguson R, Guo Z, Thomas-Fowlkes BS, Felix JP, Liu J, Kohler M, Priest B, Hampton C, Pai LY, Corona A, Metzger J, Tong V, Joshi EM, Xu L, Owens K, Maloney K, Sullivan K, and Pasternak A
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- Animals, Heterocyclic Compounds chemical synthesis, Rats, Rats, Inbred SHR, Diuretics pharmacology, Drug Design, Enzyme Inhibitors pharmacology, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacology, Potassium Channels, Inwardly Rectifying antagonists & inhibitors, Sulfones pharmacology
- Abstract
A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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6. Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.
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Zhu Y, de Jesus RK, Tang H, Walsh SP, Jiang J, Gu X, Teumelsan N, Shahripour A, Pio B, Ding FX, Ha S, Priest BT, Swensen AM, Alonso-Galicia M, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Zhou X, Pai LY, Hampton C, Hernandez M, Owens K, Ehrhart J, Roy S, Kaczorowski GJ, Yang L, Parmee ER, Sullivan K, Garcia ML, and Pasternak A
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- Animals, Diuresis drug effects, Dogs, Heart Failure drug therapy, Humans, Hypertension drug therapy, Macaca mulatta, Oxazines pharmacokinetics, Potassium Channels, Inwardly Rectifying metabolism, Rats, Sprague-Dawley, Transcriptional Regulator ERG antagonists & inhibitors, Transcriptional Regulator ERG metabolism, Oxazines chemistry, Oxazines pharmacology, Potassium Channels, Inwardly Rectifying antagonists & inhibitors
- Abstract
Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads., (Published by Elsevier Ltd.)
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- 2016
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7. The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype.
- Author
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Hampton C, Zhou X, Priest BT, Pai LY, Felix JP, Thomas-Fowlkes B, Liu J, Kohler M, Xiao J, Corona A, Price O, Gill C, Shah K, Rasa C, Tong V, Owens K, Ormes J, Tang H, Roy S, Sullivan KA, Metzger JM, Alonso-Galicia M, Kaczorowski GJ, Pasternak A, and Garcia ML
- Subjects
- Animals, Bartter Syndrome drug therapy, Benzimidazoles pharmacology, Benzofurans therapeutic use, Biphenyl Compounds, Dogs, Dose-Response Relationship, Drug, Drug Synergism, Female, HEK293 Cells, Humans, Hydrochlorothiazide pharmacology, Male, Piperazines therapeutic use, Potassium Channel Blockers therapeutic use, Rats, Tetrazoles pharmacology, Bartter Syndrome physiopathology, Benzofurans pharmacology, Blood Pressure drug effects, Phenotype, Piperazines pharmacology, Potassium Channel Blockers pharmacology, Potassium Channels, Inwardly Rectifying antagonists & inhibitors
- Abstract
The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2016
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8. Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure.
- Author
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Tang H, Zhu Y, Teumelsan N, Walsh SP, Shahripour A, Priest BT, Swensen AM, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Pai LY, Hampton C, Corona A, Hernandez M, Metzger J, Forrest M, Zhou X, Owens K, Tong V, Parmee E, Roy S, Kaczorowski GJ, Yang L, Alonso-Galicia M, Garcia ML, and Pasternak A
- Abstract
ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.
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- 2016
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9. Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation.
- Author
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Walsh SP, Shahripour A, Tang H, de Jesus RK, Teumelsan N, Zhu Y, Frie J, Priest BT, Swensen AM, Alonso-Galicia M, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Zhou X, Pai LY, Hampton C, Hernandez M, Owens K, Ehrhart J, Roy S, Kaczorowski GJ, Yang L, Garcia ML, and Pasternak A
- Subjects
- Heterocyclic Compounds chemistry, Piperazines chemistry, Structure-Activity Relationship, ERG1 Potassium Channel physiology, Heterocyclic Compounds pharmacology, Piperazines pharmacology
- Abstract
Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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10. Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.
- Author
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Hoyt SB, Petrilli W, London C, Liang GB, Tata J, Hu Q, Yin L, van Koppen CJ, Hartmann RW, Struthers M, Wisniewski T, Ren N, Bopp C, Sok A, Cai TQ, Stribling S, Pai LY, Ma X, Metzger J, Verras A, McMasters D, Chen Q, Tung E, Tang W, Salituro G, Buist N, Clemas J, Zhou G, Gibson J, Maxwell CA, Lassman M, McLaughlin T, Castro-Perez J, Szeto D, Forrest G, Hajdu R, Rosenbach M, and Xiong Y
- Abstract
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
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- 2015
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11. Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation.
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Walsh SP, Shahripour A, Tang H, Teumelsan N, Frie J, Zhu Y, Priest BT, Swensen AM, Liu J, Margulis M, Visconti R, Weinglass A, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Alonso-Galicia M, Zhou X, Pai LY, Corona A, Hampton C, Hernandez M, Bentley R, Chen J, Shah K, Metzger J, Forrest M, Owens K, Tong V, Ha S, Roy S, Kaczorowski GJ, Yang L, Parmee E, Garcia ML, Sullivan K, and Pasternak A
- Abstract
A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.
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- 2015
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12. Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.
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Hoyt SB, Park MK, London C, Xiong Y, Tata J, Bennett DJ, Cooke A, Cai J, Carswell E, Robinson J, MacLean J, Brown L, Belshaw S, Clarkson TR, Liu K, Liang GB, Struthers M, Cully D, Wisniewski T, Ren N, Bopp C, Sok A, Cai TQ, Stribling S, Pai LY, Ma X, Metzger J, Verras A, McMasters D, Chen Q, Tung E, Tang W, Salituro G, Buist N, Kuethe J, Rivera N, Clemas J, Zhou G, Gibson J, Maxwell CA, Lassman M, McLaughlin T, Castro-Perez J, Szeto D, Forrest G, Hajdu R, Rosenbach M, and Ali A
- Abstract
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
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- 2015
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13. Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.
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Garcia ML, Priest BT, Alonso-Galicia M, Zhou X, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Liu J, Swensen A, Pai LY, Xiao J, Hernandez M, Hoagland K, Owens K, Tang H, de Jesus RK, Roy S, Kaczorowski GJ, and Pasternak A
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Dogs, Dose-Response Relationship, Drug, Female, HEK293 Cells, Humans, Madin Darby Canine Kidney Cells, Male, Natriuresis physiology, Rats, Rats, Sprague-Dawley, Diuresis drug effects, Diuresis physiology, Natriuresis drug effects, Potassium Channel Blockers pharmacology, Potassium Channels, Inwardly Rectifying antagonists & inhibitors, Potassium Channels, Inwardly Rectifying physiology
- Abstract
The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.
- Published
- 2014
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14. Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one.
- Author
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Tang H, de Jesus RK, Walsh SP, Zhu Y, Yan Y, Priest BT, Swensen AM, Alonso-Galicia M, Felix JP, Brochu RM, Bailey T, Thomas-Fowlkes B, Zhou X, Pai LY, Hampton C, Hernandez M, Owens K, Roy S, Kaczorowski GJ, Yang L, Garcia ML, and Pasternak A
- Subjects
- Animals, Benzofurans pharmacokinetics, Diuresis drug effects, Drug Discovery, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ether-A-Go-Go Potassium Channels metabolism, Humans, Potassium Channels, Inwardly Rectifying metabolism, Rats, Rats, Sprague-Dawley, Tetrazoles chemistry, Tetrazoles pharmacokinetics, Tetrazoles pharmacology, Benzofurans chemistry, Benzofurans pharmacology, Potassium Channels, Inwardly Rectifying antagonists & inhibitors
- Abstract
A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
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- 2013
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15. Evaluation of selective inhibitors of 11β-HSD1 for the treatment of hypertension.
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Bauman DR, Whitehead A, Contino LC, Cui J, Garcia-Calvo M, Gu X, Kevin N, Ma X, Pai LY, Shah K, Shen X, Stribling S, Zokian HJ, Metzger J, Shevell DE, and Waddell ST
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- Animals, Humans, Mice, Mice, Knockout, Rats, Rats, Inbred SHR, 11-beta-Hydroxysteroid Dehydrogenase Type 1 antagonists & inhibitors, Enzyme Inhibitors pharmacology, Hypertension drug therapy, Hypertension enzymology, Triazoles pharmacology
- Abstract
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11β-HSD1 inhibitors, we examined a set of 11β-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11β-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11β-HSD1 independent pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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16. A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors.
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Shen HC, Ding FX, Deng Q, Xu S, Tong X, Zhang X, Chen Y, Zhou G, Pai LY, Alonso-Galicia M, Roy S, Zhang B, Tata JR, Berger JP, and Colletti SL
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- Aniline Compounds chemical synthesis, Aniline Compounds pharmacokinetics, Animals, Binding Sites, Computer Simulation, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Epoxide Hydrolases metabolism, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring pharmacokinetics, Humans, Isoxazoles chemical synthesis, Isoxazoles pharmacokinetics, Protein Binding, Rats, Structure-Activity Relationship, Amides chemistry, Aniline Compounds chemistry, Enzyme Inhibitors chemistry, Epoxide Hydrolases antagonists & inhibitors, Heterocyclic Compounds, 2-Ring chemistry, Isoxazoles chemistry
- Abstract
Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationship (SAR) study was focused on improving the sEH inhibitory activity. Aminobenzisoxazoles emerged to be the optimal series, of which a potent human sEH inhibitor 7t was identified with a good pharmacokinetics (PK) profile. The strategy of employing aminoheterocycles as amide replacements may represent a general approach to develop mimics of known hydrolase or protease inhibitors containing an amide moiety.
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- 2009
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17. Discovery of 3,3-disubstituted piperidine-derived trisubstituted ureas as highly potent soluble epoxide hydrolase inhibitors.
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Shen HC, Ding FX, Deng Q, Xu S, Chen HS, Tong X, Tong V, Zhang X, Chen Y, Zhou G, Pai LY, Alonso-Galicia M, Zhang B, Roy S, Tata JR, Berger JP, and Colletti SL
- Subjects
- 8,11,14-Eicosatrienoic Acid analogs & derivatives, 8,11,14-Eicosatrienoic Acid blood, 8,11,14-Eicosatrienoic Acid metabolism, Animals, Blood Pressure drug effects, Humans, Models, Molecular, Protein Binding, Rats, Rats, Inbred SHR, Structure-Activity Relationship, Urea therapeutic use, Epoxide Hydrolases antagonists & inhibitors, Epoxide Hydrolases metabolism, Hypertension drug therapy, Piperidines chemistry, Urea analogs & derivatives, Urea pharmacology
- Abstract
3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.
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- 2009
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18. Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement.
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Shen HC, Ding FX, Wang S, Deng Q, Zhang X, Chen Y, Zhou G, Xu S, Chen HS, Tong X, Tong V, Mitra K, Kumar S, Tsai C, Stevenson AS, Pai LY, Alonso-Galicia M, Chen X, Soisson SM, Roy S, Zhang B, Tata JR, Berger JP, and Colletti SL
- Subjects
- Animals, Biological Availability, Cell Line, Crystallography, X-Ray, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System metabolism, Eicosanoids metabolism, Epoxy Compounds metabolism, Humans, In Vitro Techniques, Ion Channels antagonists & inhibitors, Ion Channels metabolism, Kidney drug effects, Kidney metabolism, Mesenteric Arteries drug effects, Mesenteric Arteries physiology, Models, Molecular, Molecular Conformation, Muscle Relaxation, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Piperidines pharmacokinetics, Piperidines pharmacology, Rats, Rats, Inbred SHR, Solubility, Stereoisomerism, Structure-Activity Relationship, Urea pharmacokinetics, Urea pharmacology, Epoxide Hydrolases antagonists & inhibitors, Piperidines chemical synthesis, Urea analogs & derivatives, Urea chemical synthesis
- Abstract
4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.
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- 2009
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19. Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors.
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Shen HC, Ding FX, Wang S, Xu S, Chen HS, Tong X, Tong V, Mitra K, Kumar S, Zhang X, Chen Y, Zhou G, Pai LY, Alonso-Galicia M, Chen X, Zhang B, Tata JR, Berger JP, and Colletti SL
- Subjects
- Animals, Antihypertensive Agents chemistry, Antihypertensive Agents pharmacokinetics, Cell Line, Drug Discovery, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Epoxide Hydrolases metabolism, Humans, Rats, Rats, Inbred SHR, Structure-Activity Relationship, Urea chemical synthesis, Urea pharmacokinetics, Amines chemistry, Antihypertensive Agents chemical synthesis, Enzyme Inhibitors chemical synthesis, Epoxide Hydrolases antagonists & inhibitors, Spiro Compounds chemistry, Urea analogs & derivatives
- Abstract
Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.
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- 2009
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20. Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice.
- Author
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Clark JA, Flick RB, Pai LY, Szalayova I, Key S, Conley RK, Deutch AY, Hutson PH, and Mezey E
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- 5-Hydroxytryptophan analysis, Amino Acid Sequence, Animals, Antibody Specificity, Dexamethasone pharmacology, Enzyme Induction drug effects, Female, Frontal Lobe drug effects, Humans, Immune Sera, Mice, Mice, Inbred C57BL, Mifepristone pharmacology, Molecular Sequence Data, Nerve Tissue Proteins analysis, Nerve Tissue Proteins genetics, Nerve Tissue Proteins immunology, Ovariectomy, Peptide Fragments immunology, Protein Isoforms biosynthesis, Protein Isoforms genetics, Protein Isoforms immunology, RNA, Messenger biosynthesis, Raphe Nuclei drug effects, Rats, Rats, Sprague-Dawley, Tryptophan Hydroxylase genetics, Tryptophan Hydroxylase immunology, 5-Hydroxytryptophan biosynthesis, Dexamethasone analogs & derivatives, Frontal Lobe chemistry, Nerve Tissue Proteins biosynthesis, Raphe Nuclei enzymology, Tryptophan Hydroxylase analysis, Tryptophan Hydroxylase biosynthesis
- Abstract
Considerable attention has focused on regulation of central tryptophan hydroxylase (TPH) activity and protein expression. At the time of these earlier studies, it was thought that there was a single central TPH isoform. However, with the recent identification of TPH2, it becomes important to distinguish between regulatory effects on the protein expression and activity of the two isoforms. We have generated a TPH2-specific polyclonal antiserum (TPH2-6361) to study regulation of TPH2 at the protein level and to examine the distribution of TPH2 expression in rodent and human brain. TPH2 immunoreactivity (IR) was detected throughout the raphe nuclei, in lateral hypothalamic nuclei and in the pineal body of rodent and human brain. In addition, a prominent TPH2-IR fiber network was found in the human median eminence. We recently reported that glucocorticoid treatment of C57/Bl6 mice for 4 days markedly decreased TPH2 messenger RNA levels in the raphe nuclei, whereas TPH1 mRNA was unaffected. The glucocorticoid-elicited inhibition of TPH2 gene expression was blocked by co-administration of the glucocorticoid receptor antagonist mifepristone (RU-486). Using TPH2-6361, we have extended these findings to show a dose-dependent decrease in raphe TPH2 protein levels in response to 4 days of treatment with dexamethasone; this effect was blocked by co-administration of mifepristone. Moreover, the glucocorticoid-elicited inhibition of TPH2 was functionally significant: serotonin synthesis was significantly reduced in the frontal cortex of glucocorticoid-treated mice, an effect that was blocked by mifepristone co-administration. This study provides further evidence for the glucocorticoid regulation of serotonin biosynthesis via inhibition of TPH2 expression, and suggest that elevated glucocorticoid levels may be relevant to the etiology of psychiatric diseases, such as depression, where hypothalamic-pituitary-adrenal axis dysregulation has been documented.
- Published
- 2008
- Full Text
- View/download PDF
21. Cortactin overexpression in the esophageal squamous cell carcinoma and its involvement in the carcinogenesis.
- Author
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Hsu NY, Yeh KT, Chiang IP, Pai LY, Chen CY, and Ho HC
- Subjects
- Adult, Aged, Animals, Carcinoma, Squamous Cell metabolism, Case-Control Studies, Cohort Studies, Disease Models, Animal, Female, Gene Amplification, Humans, Male, Mice, Middle Aged, Neoplasm Invasiveness pathology, Neoplasm Staging, Prognosis, RNA, Messenger analysis, Risk Assessment, Sensitivity and Specificity, Survival Analysis, Biomarkers, Tumor metabolism, Carcinoma, Squamous Cell pathology, Cortactin metabolism, Esophageal Neoplasms metabolism, Esophageal Neoplasms pathology, Precancerous Conditions metabolism, Precancerous Conditions pathology
- Abstract
The aim of this study is to examine whether dysregulated expression of cortactin occurs in esophageal squamous cell carcinoma (ESCC) and is involved in the development of ESCCs. An immunohistochemistry study for cortactin expression was performed on 46 pairs of surgically resected non-tumor and ESCC tumor tissues and murine tumors of esophagi induced by a carcinogen. The results show increased cortactin expression in 20 and in 22 to a lesser extent, out of a total 46 ESCC tumor tissues. Increased cortactin was also detected in the premalignant lesions, the early stage dysplasia and carcinoma in situ, of ESCC tumor tissues. Differential polymerase chain reaction results showed slight increases in the EMS1 gene only in two of 10 ESCC tumor tissues, suggesting that EMS1 gene amplification is not the only mechanism for cortactin overexpression. In the mouse model induced by treatment with 4-nitroquinoline 1-oxide and arecoline, increased cortactin was detected in the epithelia with hyperkeratosis, papillomas, and ESCCs with invasion into the submucosa, respectively. Overall, we observed cortactin overexpression in early and late stages of human ESCCs and carcinogen-induced murine ESCCs, suggesting a role for cortactin in esophageal carcinogenesis.
- Published
- 2008
- Full Text
- View/download PDF
22. Estrogen receptor ligands. Part 16: 2-Aryl indoles as highly subtype selective ligands for ERalpha.
- Author
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Dykstra KD, Guo L, Birzin ET, Chan W, Yang YT, Hayes EC, DaSilva CA, Pai LY, Mosley RT, Kraker B, Fitzgerald PM, DiNinno F, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Breast Neoplasms drug therapy, Cell Line, Tumor, Estrogen Antagonists chemistry, Estrogen Antagonists pharmacology, Female, Humans, Inhibitory Concentration 50, Ligands, Uterus drug effects, Estrogen Receptor alpha antagonists & inhibitors, Indoles chemistry, Indoles pharmacokinetics
- Abstract
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
- Published
- 2007
- Full Text
- View/download PDF
23. Estrogen receptor ligands. Part 14: application of novel antagonist side chains to existing platforms.
- Author
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Blizzard TA, Morgan JD 2nd, Chan W, Birzin ET, Pai LY, Hayes EC, DaSilva CA, Mosley RT, Yang YT, Rohrer SP, Dininno F, and Hammond ML
- Subjects
- Animals, Ligands, Rats, Estrogen Receptor alpha antagonists & inhibitors, Oxathiins chemistry, Selective Estrogen Receptor Modulators chemistry, Selective Estrogen Receptor Modulators pharmacology
- Abstract
Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
- Published
- 2005
- Full Text
- View/download PDF
24. Estrogen receptor ligands. Part 13: Dihydrobenzoxathiin SERAMs with an optimized antagonist side chain.
- Author
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Blizzard TA, DiNinno F, Chen HY, Kim S, Wu JY, Chan W, Birzin ET, Yang YT, Pai LY, Hayes EC, DaSilva CA, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Animals, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cell Line, Tumor, Dose-Response Relationship, Drug, Estrogen Antagonists chemical synthesis, Estrogen Antagonists pharmacology, Female, Humans, Oxathiins pharmacology, Rats, Receptors, Estrogen metabolism, Selective Estrogen Receptor Modulators pharmacology, Structure-Activity Relationship, Uterus drug effects, Uterus growth & development, Oxathiins chemical synthesis, Receptors, Estrogen chemistry, Selective Estrogen Receptor Modulators chemical synthesis
- Abstract
An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.
- Published
- 2005
- Full Text
- View/download PDF
25. Differential hormonal regulation of tryptophan hydroxylase-2 mRNA in the murine dorsal raphe nucleus.
- Author
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Clark JA, Pai LY, Flick RB, and Rohrer SP
- Subjects
- Animals, Dexamethasone pharmacology, Estradiol pharmacology, Female, Glucocorticoids pharmacology, Hormone Antagonists pharmacology, In Situ Hybridization, Male, Mice, Mice, Inbred C57BL, Mifepristone pharmacology, Organ Size drug effects, Ovariectomy, Raphe Nuclei drug effects, Raphe Nuclei enzymology, Reverse Transcriptase Polymerase Chain Reaction, Uterus anatomy & histology, Uterus drug effects, Hormones pharmacology, RNA, Messenger biosynthesis, Raphe Nuclei metabolism, Tryptophan Hydroxylase biosynthesis
- Abstract
Background: Recently a novel tryptophan hydroxylase isoform (TPH2) was identified and shown to be highly expressed in the central nervous system (CNS). Hormonal effects on TPH2 mRNA expression in the rodent dorsal raphe nucleus (DRN) are unknown., Methods: In situ hybridization histochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) were used to assess the effects of dexamethasone or estradiol on TPH2 mRNA levels in the DRN of C57/Bl6 mice., Results: Dexamethasone reduced TPH2 mRNA levels in the DRN of both ovx female and intact male mice. Reduction of TPH2 mRNA in the DRN was blocked by co-administration of mifepristone. Estradiol had no detectable effect on TPH2 mRNA levels in the DRN., Conclusions: TPH2 mRNA is regulated by glucocorticoids but not estradiol in the mouse DRN. Glucocorticoid-mediated reduction of TPH2 message may have relevance to the etiology of major depression, psychotic major depression in particular, where elevated glucocorticoids are one hallmark of the disease.
- Published
- 2005
- Full Text
- View/download PDF
26. Estrogen receptor-beta regulates tryptophan hydroxylase-1 expression in the murine midbrain raphe.
- Author
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Gundlah C, Alves SE, Clark JA, Pai LY, Schaeffer JM, and Rohrer SP
- Subjects
- Animals, Cells, Cultured, Estrogen Receptor alpha genetics, Estrogen Receptor alpha physiology, Estrogen Receptor beta genetics, Immunohistochemistry, In Situ Hybridization, Mesencephalon enzymology, Mice, Mice, Inbred C57BL, Neurons metabolism, Ovariectomy, Raphe Nuclei enzymology, Serotonin physiology, Estrogen Receptor beta physiology, Mesencephalon metabolism, Raphe Nuclei metabolism, Tryptophan Hydroxylase biosynthesis
- Abstract
Background: Distinct expression patterns of estrogen receptor (ER)-alpha and ER-beta are displayed in the murine central nervous system. ER-beta is the predominant form of the receptor expressed in the murine midbrain dorsal raphe nucleus (DRN). Tryptophan hydroxylase (TPH) is abundantly expressed in the serotonergic neurons of the DRN and is regulated by estrogen in both the monkey and the guinea pig., Methods: In this study we used immunocytochemistry to show that ER-beta and TPH are colocalized in the serotonergic cells of the murine DRN. We utilized the ER-alpha and ER-beta gene deletion mouse models and in situ hybridization to demonstrate that ER-beta is responsible for regulating TPH1 mRNA expression., Results: Estrogen increased TPH1 mRNA expression in the DRN of wild type and ER-alpha knockout mice (alpha-ERKO) but not ER-beta knockouts (beta-ERKO)., Conclusions: These data indicate that ER-beta is responsible for mediating estrogen regulated TPH1 expression in the murine DRN.
- Published
- 2005
- Full Text
- View/download PDF
27. Estrogen receptor ligands. Part 10: Chromanes: old scaffolds for new SERAMs.
- Author
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Tan Q, Blizzard TA, Morgan JD 2nd, Birzin ET, Chan W, Yang YT, Pai LY, Hayes EC, DaSilva CA, Warrier S, Yudkovitz J, Wilkinson HA, Sharma N, Fitzgerald PM, Li S, Colwell L, Fisher JE, Adamski S, Reszka AA, Kimmel D, DiNinno F, Rohrer SP, Freedman LP, Schaeffer JM, and Hammond ML
- Subjects
- Animals, Binding Sites, Cell Line, Female, Gene Expression drug effects, Humans, Ligands, Models, Chemical, Molecular Structure, Organ Size, Protein Binding, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Uterus drug effects, Chromans chemistry, Chromans pharmacology, Estrogen Receptor alpha metabolism, Selective Estrogen Receptor Modulators chemistry, Selective Estrogen Receptor Modulators pharmacology
- Abstract
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
- Published
- 2005
- Full Text
- View/download PDF
28. Estrogen receptor ligands. Part 11: Synthesis and activity of isochromans and isothiochromans.
- Author
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Liu J, Birzin ET, Chan W, Yang YT, Pai LY, Dasilva C, Hayes EC, Mosley RT, Dininno F, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Estradiol pharmacology, Female, Humans, Inhibitory Concentration 50, Ligands, Models, Molecular, Protein Binding, Protein Isoforms, Structure-Activity Relationship, Uterus drug effects, Uterus growth & development, Chromans chemical synthesis, Chromans pharmacology, Estrogen Receptor alpha metabolism
- Abstract
The ring oxygen and sulfur analogs of lasofoxifene, 1a and 1b, were synthesized in an attempt to impart ERalpha selectivity, as found in the closely related dihydrobenzoxathiin compound I, recently discovered in these laboratories. The resulting isochroman and isothiochroman compounds were found to exhibit equipotent binding affinities to the ER isoforms and were less active in the inhibition of estradiol-triggered uterine growth when compared to I and lasofoxifene.
- Published
- 2005
- Full Text
- View/download PDF
29. Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers.
- Author
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Blizzard TA, Dininno F, Morgan JD 2nd, Chen HY, Wu JY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Fitzgerald PM, Sharma N, Li Y, Zhang Z, Hayes EC, Dasilva CA, Tang W, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Ligands, Models, Molecular, Oxathiins chemistry, Receptors, Estrogen metabolism, Oxathiins pharmacology, Pyrrolidines chemistry, Receptors, Estrogen drug effects, Selective Estrogen Receptor Modulators pharmacology
- Abstract
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
- Published
- 2005
- Full Text
- View/download PDF
30. Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains.
- Author
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Blizzard TA, DiNinno F, Morgan JD 2nd, Chen HY, Wu JY, Gude C, Kim S, Chan W, Birzin ET, Tien Yang Y, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Animals, Bridged Bicyclo Compounds pharmacology, Female, Kinetics, Models, Molecular, Molecular Conformation, Selective Estrogen Receptor Modulators chemistry, Selective Estrogen Receptor Modulators pharmacology, Structure-Activity Relationship, Uterus drug effects, Bridged Bicyclo Compounds chemistry, Ligands, Receptors, Estrogen metabolism, Selective Estrogen Receptor Modulators metabolism
- Abstract
A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
- Published
- 2004
- Full Text
- View/download PDF
31. Estrogen receptor ligands. Part 8: Dihydrobenzoxathiin SERAMs with heteroatom-substituted side chains.
- Author
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Blizzard TA, DiNinno F, Morgan JD 2nd, Wu JY, Chen HY, Kim S, Chan W, Birzin ET, Yang YT, Pai LY, Zhang Z, Hayes EC, DaSilva CA, Tang W, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Animals, Female, Kinetics, Ligands, Models, Molecular, Molecular Conformation, Selective Estrogen Receptor Modulators chemistry, Selective Estrogen Receptor Modulators pharmacology, Structure-Activity Relationship, Uterus drug effects, Receptors, Estrogen metabolism, Selective Estrogen Receptor Modulators metabolism
- Abstract
A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
- Published
- 2004
- Full Text
- View/download PDF
32. Estrogen receptor ligands. Part 5: The SAR of dihydrobenzoxathiins containing modified basic side chains.
- Author
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Tan Q, Birzin ET, Chan W, Tien Yang Y, Pai LY, Hayes EC, DaSilva CA, DiNinno F, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Binding Sites, Cell Line, Tumor, Estrogen Antagonists pharmacology, Estrogen Receptor alpha antagonists & inhibitors, Estrogen Receptor beta antagonists & inhibitors, Humans, Ligands, Oxathiins pharmacology, Structure-Activity Relationship, Estrogen Antagonists chemical synthesis, Oxathiins chemical synthesis, Receptors, Estrogen metabolism
- Abstract
Dihydrobenzoxathiin analogs (1-11) with modifications on the basic side chain region were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. The compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, similar to the original lead compound I. Many of the compounds also maintained high potency in the inhibition of human carcinoma MCF-7 cell growth. However, all were less potent in the inhibition of estradiol-triggered uterine growth. This work demonstrates the sensitive nature of modification to the antagonist basic side chain region.
- Published
- 2004
- Full Text
- View/download PDF
33. Estrogen receptor ligands. Part 6: Synthesis and binding affinity of dihydrobenzodithiins.
- Author
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Tan Q, Birzin ET, Chan W, Yang YT, Pai LY, Hayes EC, DaSilva CA, DiNinno F, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Animals, Binding Sites, Cells, Cultured, Estrogen Receptor alpha, Estrogen Receptor beta, Female, Heterocyclic Compounds, 2-Ring pharmacology, Inhibitory Concentration 50, Ligands, Models, Biological, Piperidines pharmacology, Rats, Selective Estrogen Receptor Modulators pharmacology, Structure-Activity Relationship, Uterus drug effects, Uterus metabolism, Heterocyclic Compounds, 2-Ring chemical synthesis, Piperidines chemical synthesis, Receptors, Estrogen metabolism, Selective Estrogen Receptor Modulators chemical synthesis
- Abstract
Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model.
- Published
- 2004
- Full Text
- View/download PDF
34. Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators.
- Author
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Kim S, Wu JY, Birzin ET, Frisch K, Chan W, Pai LY, Yang YT, Mosley RT, Fitzgerald PM, Sharma N, Dahllund J, Thorsell AG, DiNinno F, Rohrer SP, Schaeffer JM, and Hammond ML
- Subjects
- Animals, Binding Sites, Binding, Competitive, Cell Line, Crystallography, X-Ray, Estrogen Receptor alpha, Estrogen Receptor beta, Female, Humans, Ligands, Models, Molecular, Molecular Conformation, Organ Size drug effects, Oxathiins chemistry, Oxathiins pharmacology, Receptors, Estrogen drug effects, Receptors, Estrogen metabolism, Selective Estrogen Receptor Modulators chemistry, Selective Estrogen Receptor Modulators pharmacology, Stereoisomerism, Structure-Activity Relationship, Transcriptional Activation, Uterus drug effects, Oxathiins chemical synthesis, Selective Estrogen Receptor Modulators chemical synthesis
- Abstract
The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
- Published
- 2004
- Full Text
- View/download PDF
Catalog
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