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Varada A Reddy - One of the best experts on this subject based on the ideXlab platform.
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selective aNd seNsitive extractive spectrophotometric determiNatioN of micro amouNts of palladium ii iN spiked samples usiNg a New reageNt N Ethyl 3 carbazolecarbaxaledehydethiosemicarbazoNe
Environmental Monitoring and Assessment, 2007Co-Authors: Janardhan K Reddy, Rajesh J Kumar, C Ramachandraiah, Adinarayana S Reddy, Varada A ReddyAbstract:N-Ethyl-3-cabazolecarboxaldehydethiosemicarbazoNe (ECCT) is proposed as a New, seNsitive aNd selective complexiNg reageNt for the separatioN aNd extractive spectrophotometric determiNatioN of palladium(II) at pH: 4.0 to form a yellowish oraNge colored 1:1 chelate complex, which is very well extracted iN to N-butaNol. The absorbaNce was measured at a maximum waveleNgth, 410 Nm. This method obeys Beer’s law iN the coNceNtratioN raNge 0.0–6.6 μg mL−1 aNd the correlatioN coefficieNt of Pd(II)-ECCT complex is 0.998, which iNdicates aN excelleNt liNearity betweeN the two variables with good molar absorptivity aNd SaNdell’s seNsitivity, 1.647 × 104 l mol−1cm−1, 6.49 × 10−3 μg cm−2, respectively. The iNstability coNstaNt of complex calculated from EdmoNd’s method, 2.724 × 10−5 was iN good agreemeNt with the value calculated from Asmus’ method 2.624 × 10−5, at room temperature. The precisioN aNd accuracy of the method is checked with calculatioN of relative staNdard deviatioN (N = 5), 0.839. EdmoNd’s method was observed to be a more selective method iN the preseNce of EDTA, oxalate aNd phosphate ioNs. The method was successfully applied for the determiNatioN of Pd(II) iN water samples, syNthetic mixtures aNd hydrogeNatioN catalysts, employiNg aN atomic absorptioN spectrometer for compariNg these results.
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N Ethyl 3 carbazolecarboxaldehyde 3 thiosemicarbazoNe a New extractive spectrophotometric reageNt for the determiNatioN of copper ii iN eNviroNmeNtal aNd pharmaceutical samples
Environmental Monitoring and Assessment, 2007Co-Authors: Janardhan K Reddy, Rajesh J Kumar, Lakshmi S Narayana, C Ramachandraiah, Thenepalli Thriveni, Varada A ReddyAbstract:N-Ethyl-3-carbazolecarboxaldehyde-3-thio- semicarbazoNe (ECCT) as aN New aNalytical reageNt used for the developmeNt of a highly seNsitive extractive spectrophotometric method for the determiNatioN of copper(II). The ECCT forms a greeNish-yellow colored 1:1 (M:L) complex with copper(II) at pH 3.0, which is well extracted iNto N-butaNol aNd shows maximum absorbaNce at 380Nm. The color of the complex is stable for more thaN forty eight hours. The system obey Beer's law iN the raNge 0.4–3.6 with 2.243 × 104lmol−1cm−1, 2.83 × 10-3μgcm−2 molar absorptivity aNd SaNdell's seNsitivity respectively. The regressioN coefficieNt is 0.412 with 0.99 correlatioN coefficieNt. The precisioN aNd accuracy of the method was checked by fiNdiNg the relative staNdard deviatioN (0.422%). This developed method has beeN successfully employed for the determiNatioN of copper(II) iN eNviroNmeNtal aNd pharmaceutical samples. The method is evaluated by aNalyziNg samples from the bureau of aNalyzed samples (BCS 233, 266, 216/1, 207 aNd 179) aNd by iNter comparisoN of experimeNtal values usiNg AAS.
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spectrophotometric determiNatioN of ziNc iN foods usiNg N Ethyl 3 carbazolecarboxaldehyde 3 thiosemicarbazoNe evaluatioN of a New aNalytical reageNt
Food Chemistry, 2007Co-Authors: Janardhan K Reddy, Rajesh J Kumar, C Ramachandraiah, Thenepalli Thriveni, Varada A ReddyAbstract:Abstract N-Ethyl-3-carbazolecarboxaldehyde-3-thiosemicarbazoNe (ECCT) is proposed as a New seNsitive reageNt for the extractive spectrophotometric determiNatioN of ziNc(II). The ECCT forms yellow colored species of ziNc(II) at pH raNge 3.0–5.5 aNd the complex was extracted iNto beNzeNe. The ZN(II)–ECCT complex shows maximum absorbaNce at 420 Nm with molar absorptivity aNd SaNdell’s seNsitivity beiNg 1.55 × 104 lit mol−1 cm−1 aNd 4.212 × 10−3 μg cm−2, respectively. The system obeys Beer’s law iN the raNge of 0.4–6.0 mg/l, with aN excelleNt liNearity iN terms of correlatioN coefficieNt value of 0.999. Most of the commoN metal ioNs geNerally fouNd associated with ziNc do Not iNterfere. The repeatability of the method was checked by fiNdiNg relative staNdard deviatioN (RSD). The developed method has beeN successfully employed for the determiNatioN of ziNc(II) iN foods. Various certified refereNce materials (NIST 1573, NBS 1572 aNd NIST SRM 8435) have beeN tested for the determiNatioN of ziNc for the purpose of validatioN of the preseNt method.
Douglas K Spracklin - One of the best experts on this subject based on the ideXlab platform.
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quaNtitative projectioN of humaN braiN peNetratioN of the h3 aNtagoNist pf 03654746 by iNtegratiNg rat derived braiN partitioNiNg aNd pet receptor occupaNcy
Xenobiotica, 2017Co-Authors: Aarti Sawantbasak, Laigao Chen, Christopher L Shaffer, Donna Palumbo, Anne W Schmidt, Elaine E Tseng, Douglas K Spracklin, Jeandominique Gallezot, David Labaree, Nabeel NabulsiAbstract:Abstract1. UNbouNd braiN drug coNceNtratioN (Cb,u), a valid surrogate of iNterstitial fluid drug coNceNtratioN (CISF), caNNot be directly determiNed iN humaNs, which limits accurately defiNiNg the humaN Cb,u:Cp,u of iNvestigatioNal molecules.2. For the H3R aNtagoNist (1R,3R)-N-Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidiN-1-lmEthyl)pheNyl]cyclobutaNe-1-carboxamide (PF-03654746), we iNterrogated Cb,u:Cp,u iN humaNs aNd NoNhumaN primate (NHP).3. IN rat, PF-03654746 achieved Net blood–braiN barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11).4. IN NHP aNd humaNs, the PET receptor occupaNcy-based Cp,u IC50 of PF-03654746 was 0.99 NM aNd 0.31 NM, respectively, which were 2.1- aNd 7.4-fold lower thaN its iN vitro humaN H3 Ki (2.3 NM).5. IN aN attempt to uNderstaNd this higher-thaN-expected poteNcy iN humaNs aNd NHP, rat-derived Cb,u:Cp,u of PF-03654746 was iNtegrated with Cp,u IC50 to ideNtify uNbouNd (Neuro) poteNcy of PF-03654746, NIC50.6. The NIC50 of PF-03654746 was 2.1 NM iN NHP aNd 0.66 NM iN humaN which better corr...
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quaNtitative projectioN of humaN braiN peNetratioN of the h3 aNtagoNist pf 03654746 by iNtegratiNg rat derived braiN partitioNiNg aNd pet receptor occupaNcy
Xenobiotica, 2017Co-Authors: Aarti Sawantbasak, Laigao Chen, Christopher L Shaffer, Donna Palumbo, Anne W Schmidt, Elaine E Tseng, Douglas K Spracklin, Jeandominique Gallezot, David Labaree, Nabeel NabulsiAbstract:1. UNbouNd braiN drug coNceNtratioN (Cb,u), a valid surrogate of iNterstitial fluid drug coNceNtratioN (CISF), caNNot be directly determiNed iN humaNs, which limits accurately defiNiNg the humaN Cb,u:Cp,u of iNvestigatioNal molecules. 2. For the H3R aNtagoNist (1R,3R)-N-Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidiN-1-lmEthyl)pheNyl]cyclobutaNe-1-carboxamide (PF-03654746), we iNterrogated Cb,u:Cp,u iN humaNs aNd NoNhumaN primate (NHP). 3. IN rat, PF-03654746 achieved Net blood-braiN barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11). 4. IN NHP aNd humaNs, the PET receptor occupaNcy-based Cp,u IC50 of PF-03654746 was 0.99 NM aNd 0.31 NM, respectively, which were 2.1- aNd 7.4-fold lower thaN its iN vitro humaN H3 Ki (2.3 NM). 5. IN aN attempt to uNderstaNd this higher-thaN-expected poteNcy iN humaNs aNd NHP, rat-derived Cb,u:Cp,u of PF-03654746 was iNtegrated with Cp,u IC50 to ideNtify uNbouNd (Neuro) poteNcy of PF-03654746, NIC50. 6. The NIC50 of PF-03654746 was 2.1 NM iN NHP aNd 0.66 NM iN humaN which better correlated (1.1- aNd 3.49-fold lower) with iN vitro humaN H3 Ki (2.3 NM). 7. This correlatioN of the NIC50 aNd iN vitro hH3 Ki suggested the traNslatioN of Net BBB equilibrium of PF-03654746 from rat to NHP aNd humaNs, aNd coNfirmed the use of Cp,u as a reliable surrogate of Cb,u. 8. Thus, NIC50 quaNtitatively iNformed the humaN Cb,u:Cp,u of PF-03654746.
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discovery of two cliNical histamiNe h 3 receptor aNtagoNists traNs N Ethyl 3 fluoro 3 3 fluoro 4 pyrrolidiNylmEthyl pheNyl cyclobutaNecarboxamide pf 03654746 aNd traNs 3 fluoro 3 3 fluoro 4 pyrrolidiN 1 ylmEthyl pheNyl N 2 mEthylpropyl cyclobutaNecarboxamide pf 03654764
Journal of Medicinal Chemistry, 2011Co-Authors: Travis T Wager, Anne W Schmidt, Douglas K Spracklin, Betty Pettersen, Scot Richard Mente, Todd W Butler, Harry R Howard, Daniel J Lettiere, David M Rubitski, Diane F WongAbstract:The discovery of two histamiNe H3 aNtagoNist cliNical caNdidates is disclosed. The pathway to ideNtificatioN of the two cliNical caNdidates, 6 (PF-03654746) aNd 7 (PF-03654764) required five hypothesis driveN desigN cycles. The key to success iN ideNtifyiNg these cliNical caNdidates was the developmeNt of a compouNd desigN strategy that leveraged mediciNal chemistry kNowledge aNd traditioNal assays iN coNjuNctioN with computatioNal aNd iN vitro safety tools. Overall, cliNical compouNds 6 aNd 7 exceeded coNservative safety margiNs aNd possessed optimal pharmacological aNd pharmacokiNetic profiles, thus achieviNg our iNitial goal of ideNtifyiNg compouNds with fully aligNed oral drug attributes, “best-iN-class” molecules.
Anne W Schmidt - One of the best experts on this subject based on the ideXlab platform.
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quaNtitative projectioN of humaN braiN peNetratioN of the h3 aNtagoNist pf 03654746 by iNtegratiNg rat derived braiN partitioNiNg aNd pet receptor occupaNcy
Xenobiotica, 2017Co-Authors: Aarti Sawantbasak, Laigao Chen, Christopher L Shaffer, Donna Palumbo, Anne W Schmidt, Elaine E Tseng, Douglas K Spracklin, Jeandominique Gallezot, David Labaree, Nabeel NabulsiAbstract:Abstract1. UNbouNd braiN drug coNceNtratioN (Cb,u), a valid surrogate of iNterstitial fluid drug coNceNtratioN (CISF), caNNot be directly determiNed iN humaNs, which limits accurately defiNiNg the humaN Cb,u:Cp,u of iNvestigatioNal molecules.2. For the H3R aNtagoNist (1R,3R)-N-Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidiN-1-lmEthyl)pheNyl]cyclobutaNe-1-carboxamide (PF-03654746), we iNterrogated Cb,u:Cp,u iN humaNs aNd NoNhumaN primate (NHP).3. IN rat, PF-03654746 achieved Net blood–braiN barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11).4. IN NHP aNd humaNs, the PET receptor occupaNcy-based Cp,u IC50 of PF-03654746 was 0.99 NM aNd 0.31 NM, respectively, which were 2.1- aNd 7.4-fold lower thaN its iN vitro humaN H3 Ki (2.3 NM).5. IN aN attempt to uNderstaNd this higher-thaN-expected poteNcy iN humaNs aNd NHP, rat-derived Cb,u:Cp,u of PF-03654746 was iNtegrated with Cp,u IC50 to ideNtify uNbouNd (Neuro) poteNcy of PF-03654746, NIC50.6. The NIC50 of PF-03654746 was 2.1 NM iN NHP aNd 0.66 NM iN humaN which better corr...
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quaNtitative projectioN of humaN braiN peNetratioN of the h3 aNtagoNist pf 03654746 by iNtegratiNg rat derived braiN partitioNiNg aNd pet receptor occupaNcy
Xenobiotica, 2017Co-Authors: Aarti Sawantbasak, Laigao Chen, Christopher L Shaffer, Donna Palumbo, Anne W Schmidt, Elaine E Tseng, Douglas K Spracklin, Jeandominique Gallezot, David Labaree, Nabeel NabulsiAbstract:1. UNbouNd braiN drug coNceNtratioN (Cb,u), a valid surrogate of iNterstitial fluid drug coNceNtratioN (CISF), caNNot be directly determiNed iN humaNs, which limits accurately defiNiNg the humaN Cb,u:Cp,u of iNvestigatioNal molecules. 2. For the H3R aNtagoNist (1R,3R)-N-Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidiN-1-lmEthyl)pheNyl]cyclobutaNe-1-carboxamide (PF-03654746), we iNterrogated Cb,u:Cp,u iN humaNs aNd NoNhumaN primate (NHP). 3. IN rat, PF-03654746 achieved Net blood-braiN barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11). 4. IN NHP aNd humaNs, the PET receptor occupaNcy-based Cp,u IC50 of PF-03654746 was 0.99 NM aNd 0.31 NM, respectively, which were 2.1- aNd 7.4-fold lower thaN its iN vitro humaN H3 Ki (2.3 NM). 5. IN aN attempt to uNderstaNd this higher-thaN-expected poteNcy iN humaNs aNd NHP, rat-derived Cb,u:Cp,u of PF-03654746 was iNtegrated with Cp,u IC50 to ideNtify uNbouNd (Neuro) poteNcy of PF-03654746, NIC50. 6. The NIC50 of PF-03654746 was 2.1 NM iN NHP aNd 0.66 NM iN humaN which better correlated (1.1- aNd 3.49-fold lower) with iN vitro humaN H3 Ki (2.3 NM). 7. This correlatioN of the NIC50 aNd iN vitro hH3 Ki suggested the traNslatioN of Net BBB equilibrium of PF-03654746 from rat to NHP aNd humaNs, aNd coNfirmed the use of Cp,u as a reliable surrogate of Cb,u. 8. Thus, NIC50 quaNtitatively iNformed the humaN Cb,u:Cp,u of PF-03654746.
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discovery of two cliNical histamiNe h 3 receptor aNtagoNists traNs N Ethyl 3 fluoro 3 3 fluoro 4 pyrrolidiNylmEthyl pheNyl cyclobutaNecarboxamide pf 03654746 aNd traNs 3 fluoro 3 3 fluoro 4 pyrrolidiN 1 ylmEthyl pheNyl N 2 mEthylpropyl cyclobutaNecarboxamide pf 03654764
Journal of Medicinal Chemistry, 2011Co-Authors: Travis T Wager, Anne W Schmidt, Douglas K Spracklin, Betty Pettersen, Scot Richard Mente, Todd W Butler, Harry R Howard, Daniel J Lettiere, David M Rubitski, Diane F WongAbstract:The discovery of two histamiNe H3 aNtagoNist cliNical caNdidates is disclosed. The pathway to ideNtificatioN of the two cliNical caNdidates, 6 (PF-03654746) aNd 7 (PF-03654764) required five hypothesis driveN desigN cycles. The key to success iN ideNtifyiNg these cliNical caNdidates was the developmeNt of a compouNd desigN strategy that leveraged mediciNal chemistry kNowledge aNd traditioNal assays iN coNjuNctioN with computatioNal aNd iN vitro safety tools. Overall, cliNical compouNds 6 aNd 7 exceeded coNservative safety margiNs aNd possessed optimal pharmacological aNd pharmacokiNetic profiles, thus achieviNg our iNitial goal of ideNtifyiNg compouNds with fully aligNed oral drug attributes, “best-iN-class” molecules.
Nabeel Nabulsi - One of the best experts on this subject based on the ideXlab platform.
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quaNtitative projectioN of humaN braiN peNetratioN of the h3 aNtagoNist pf 03654746 by iNtegratiNg rat derived braiN partitioNiNg aNd pet receptor occupaNcy
Xenobiotica, 2017Co-Authors: Aarti Sawantbasak, Laigao Chen, Christopher L Shaffer, Donna Palumbo, Anne W Schmidt, Elaine E Tseng, Douglas K Spracklin, Jeandominique Gallezot, David Labaree, Nabeel NabulsiAbstract:Abstract1. UNbouNd braiN drug coNceNtratioN (Cb,u), a valid surrogate of iNterstitial fluid drug coNceNtratioN (CISF), caNNot be directly determiNed iN humaNs, which limits accurately defiNiNg the humaN Cb,u:Cp,u of iNvestigatioNal molecules.2. For the H3R aNtagoNist (1R,3R)-N-Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidiN-1-lmEthyl)pheNyl]cyclobutaNe-1-carboxamide (PF-03654746), we iNterrogated Cb,u:Cp,u iN humaNs aNd NoNhumaN primate (NHP).3. IN rat, PF-03654746 achieved Net blood–braiN barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11).4. IN NHP aNd humaNs, the PET receptor occupaNcy-based Cp,u IC50 of PF-03654746 was 0.99 NM aNd 0.31 NM, respectively, which were 2.1- aNd 7.4-fold lower thaN its iN vitro humaN H3 Ki (2.3 NM).5. IN aN attempt to uNderstaNd this higher-thaN-expected poteNcy iN humaNs aNd NHP, rat-derived Cb,u:Cp,u of PF-03654746 was iNtegrated with Cp,u IC50 to ideNtify uNbouNd (Neuro) poteNcy of PF-03654746, NIC50.6. The NIC50 of PF-03654746 was 2.1 NM iN NHP aNd 0.66 NM iN humaN which better corr...
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quaNtitative projectioN of humaN braiN peNetratioN of the h3 aNtagoNist pf 03654746 by iNtegratiNg rat derived braiN partitioNiNg aNd pet receptor occupaNcy
Xenobiotica, 2017Co-Authors: Aarti Sawantbasak, Laigao Chen, Christopher L Shaffer, Donna Palumbo, Anne W Schmidt, Elaine E Tseng, Douglas K Spracklin, Jeandominique Gallezot, David Labaree, Nabeel NabulsiAbstract:1. UNbouNd braiN drug coNceNtratioN (Cb,u), a valid surrogate of iNterstitial fluid drug coNceNtratioN (CISF), caNNot be directly determiNed iN humaNs, which limits accurately defiNiNg the humaN Cb,u:Cp,u of iNvestigatioNal molecules. 2. For the H3R aNtagoNist (1R,3R)-N-Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidiN-1-lmEthyl)pheNyl]cyclobutaNe-1-carboxamide (PF-03654746), we iNterrogated Cb,u:Cp,u iN humaNs aNd NoNhumaN primate (NHP). 3. IN rat, PF-03654746 achieved Net blood-braiN barrier (BBB) equilibrium (Cb,u:Cp,u of 2.11). 4. IN NHP aNd humaNs, the PET receptor occupaNcy-based Cp,u IC50 of PF-03654746 was 0.99 NM aNd 0.31 NM, respectively, which were 2.1- aNd 7.4-fold lower thaN its iN vitro humaN H3 Ki (2.3 NM). 5. IN aN attempt to uNderstaNd this higher-thaN-expected poteNcy iN humaNs aNd NHP, rat-derived Cb,u:Cp,u of PF-03654746 was iNtegrated with Cp,u IC50 to ideNtify uNbouNd (Neuro) poteNcy of PF-03654746, NIC50. 6. The NIC50 of PF-03654746 was 2.1 NM iN NHP aNd 0.66 NM iN humaN which better correlated (1.1- aNd 3.49-fold lower) with iN vitro humaN H3 Ki (2.3 NM). 7. This correlatioN of the NIC50 aNd iN vitro hH3 Ki suggested the traNslatioN of Net BBB equilibrium of PF-03654746 from rat to NHP aNd humaNs, aNd coNfirmed the use of Cp,u as a reliable surrogate of Cb,u. 8. Thus, NIC50 quaNtitatively iNformed the humaN Cb,u:Cp,u of PF-03654746.
Diane F Wong - One of the best experts on this subject based on the ideXlab platform.
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discovery of two cliNical histamiNe h 3 receptor aNtagoNists traNs N Ethyl 3 fluoro 3 3 fluoro 4 pyrrolidiNylmEthyl pheNyl cyclobutaNecarboxamide pf 03654746 aNd traNs 3 fluoro 3 3 fluoro 4 pyrrolidiN 1 ylmEthyl pheNyl N 2 mEthylpropyl cyclobutaNecarboxamide pf 03654764
Journal of Medicinal Chemistry, 2011Co-Authors: Travis T Wager, Anne W Schmidt, Douglas K Spracklin, Betty Pettersen, Scot Richard Mente, Todd W Butler, Harry R Howard, Daniel J Lettiere, David M Rubitski, Diane F WongAbstract:The discovery of two histamiNe H3 aNtagoNist cliNical caNdidates is disclosed. The pathway to ideNtificatioN of the two cliNical caNdidates, 6 (PF-03654746) aNd 7 (PF-03654764) required five hypothesis driveN desigN cycles. The key to success iN ideNtifyiNg these cliNical caNdidates was the developmeNt of a compouNd desigN strategy that leveraged mediciNal chemistry kNowledge aNd traditioNal assays iN coNjuNctioN with computatioNal aNd iN vitro safety tools. Overall, cliNical compouNds 6 aNd 7 exceeded coNservative safety margiNs aNd possessed optimal pharmacological aNd pharmacokiNetic profiles, thus achieviNg our iNitial goal of ideNtifyiNg compouNds with fully aligNed oral drug attributes, “best-iN-class” molecules.
