Pharmacological characterization of LY335979: A potent cyclopropyldibenzosuberane modulator of P-glycoprotein

James J. Starling; Robert L. Shepard; Jin Cao; Kevin L. Law; Bryan H. Norman; Julian S. Kroin; William J. Ehlhardt; Todd M. Baughman; Mark A. Winter; Michael G. Bell; Chuan Shih; Joseph Gruber; William F. Elmquist; Anne H. Dantzig

doi:10.1016/S0065-2571(96)00021-0

Pharmacological characterization of LY335979: A potent cyclopropyldibenzosuberane modulator of P-glycoprotein

James J. Starling, Robert L. Shepard, Jin Cao, Kevin L. Law, Bryan H. Norman, Julian S. Kroin, William J. Ehlhardt, Todd M. Baughman, Mark A. Winter, Michael G. Bell, Chuan Shih, Joseph Gruber, William F. Elmquist, Anne H. Dantzig

Pharmaceutics

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

Abstract

The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.

Original language	English (US)
Pages (from-to)	335-347
Number of pages	13
Journal	Advances in Enzyme Regulation
Volume	37
DOIs	https://doi.org/10.1016/S0065-2571(96)00021-0
State	Published - 1997

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Starling, J. J., Shepard, R. L., Cao, J., Law, K. L., Norman, B. H., Kroin, J. S., Ehlhardt, W. J., Baughman, T. M., Winter, M. A., Bell, M. G., Shih, C., Gruber, J., Elmquist, W. F., & Dantzig, A. H. (1997). Pharmacological characterization of LY335979: A potent cyclopropyldibenzosuberane modulator of P-glycoprotein. Advances in Enzyme Regulation, 37, 335-347. https://doi.org/10.1016/S0065-2571(96)00021-0

Starling, JJ, Shepard, RL, Cao, J, Law, KL, Norman, BH, Kroin, JS, Ehlhardt, WJ, Baughman, TM, Winter, MA, Bell, MG, Shih, C, Gruber, J, Elmquist, WF & Dantzig, AH 1997, 'Pharmacological characterization of LY335979: A potent cyclopropyldibenzosuberane modulator of P-glycoprotein', Advances in Enzyme Regulation, vol. 37, pp. 335-347. https://doi.org/10.1016/S0065-2571(96)00021-0

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title = "Pharmacological characterization of LY335979: A potent cyclopropyldibenzosuberane modulator of P-glycoprotein",

abstract = "The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.",

author = "Starling, {James J.} and Shepard, {Robert L.} and Jin Cao and Law, {Kevin L.} and Norman, {Bryan H.} and Kroin, {Julian S.} and Ehlhardt, {William J.} and Baughman, {Todd M.} and Winter, {Mark A.} and Bell, {Michael G.} and Chuan Shih and Joseph Gruber and Elmquist, {William F.} and Dantzig, {Anne H.}",

year = "1997",

doi = "10.1016/S0065-2571(96)00021-0",

language = "English (US)",

volume = "37",

pages = "335--347",

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T1 - Pharmacological characterization of LY335979

T2 - A potent cyclopropyldibenzosuberane modulator of P-glycoprotein

AU - Starling, James J.

AU - Shepard, Robert L.

AU - Cao, Jin

AU - Law, Kevin L.

AU - Norman, Bryan H.

AU - Kroin, Julian S.

AU - Ehlhardt, William J.

AU - Baughman, Todd M.

AU - Winter, Mark A.

AU - Bell, Michael G.

AU - Shih, Chuan

AU - Gruber, Joseph

AU - Elmquist, William F.

AU - Dantzig, Anne H.

PY - 1997

Y1 - 1997

N2 - The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.

AB - The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.

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SN - 2212-4926

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JO - Advances in Biological Regulation

JF - Advances in Biological Regulation

ER -

Pharmacological characterization of LY335979: A potent cyclopropyldibenzosuberane modulator of P-glycoprotein

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