Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189

Antonia F. Stepan; Tuan P. Tran; Christopher J. Helal; Maria S. Brown; Cheng Chang; Rebecca E. O'Connor; Michael De Vivo; Shawn D. Doran; Ethan L. Fisher; Stephen Jenkinson; David Karanian; Bethany L. Kormos; Raman Sharma; Gregory S. Walker; Ann S. Wright; Edward X. Yang; Michael A. Brodney; Travis T. Wager; Patrick R. Verhoest; R. Scott Obach

doi:10.1021/acsmedchemlett.7b00343

Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189

Antonia F. Stepan
, Tuan P. Tran
, Christopher J. Helal
, Maria S. Brown
, Cheng Chang
, Rebecca E. O'Connor
, Michael De Vivo
, Shawn D. Doran
, Ethan L. Fisher
, Stephen Jenkinson
, David Karanian
, Bethany L. Kormos
, Raman Sharma
, Gregory S. Walker
, Ann S. Wright
, Edward X. Yang
, Michael A. Brodney
, Travis T. Wager
, Patrick R. Verhoest
, R. Scott Obach

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

31 Scopus citations

Abstract

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.

Original language	English
Pages (from-to)	68-72
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	2
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00343
State	Published - 8 Feb 2018
Externally published	Yes

Keywords

PDE2
drug-drug interactions
late-stage oxidation
liver microsomes
renal clearance

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10.1021/acsmedchemlett.7b00343

Cite this

Stepan, A. F., Tran, T. P., Helal, C. J., Brown, M. S., Chang, C., O'Connor, R. E., De Vivo, M., Doran, S. D., Fisher, E. L., Jenkinson, S., Karanian, D., Kormos, B. L., Sharma, R., Walker, G. S., Wright, A. S., Yang, E. X., Brodney, M. A., Wager, T. T., Verhoest, P. R., & Obach, R. S. (2018). Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189. ACS Medicinal Chemistry Letters, 9(2), 68-72. https://doi.org/10.1021/acsmedchemlett.7b00343

@article{52aaa23b02f9418e8e12573c64460fc4,

title = "Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189",

abstract = "Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.",

keywords = "PDE2, drug-drug interactions, late-stage oxidation, liver microsomes, renal clearance",

author = "Stepan, \{Antonia F.\} and Tran, \{Tuan P.\} and Helal, \{Christopher J.\} and Brown, \{Maria S.\} and Cheng Chang and O'Connor, \{Rebecca E.\} and \{De Vivo\}, Michael and Doran, \{Shawn D.\} and Fisher, \{Ethan L.\} and Stephen Jenkinson and David Karanian and Kormos, \{Bethany L.\} and Raman Sharma and Walker, \{Gregory S.\} and Wright, \{Ann S.\} and Yang, \{Edward X.\} and Brodney, \{Michael A.\} and Wager, \{Travis T.\} and Verhoest, \{Patrick R.\} and Obach, \{R. Scott\}",

note = "Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = feb,

day = "8",

doi = "10.1021/acsmedchemlett.7b00343",

language = "English",

volume = "9",

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journal = "ACS Medicinal Chemistry Letters",

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Stepan, AF, Tran, TP, Helal, CJ, Brown, MS, Chang, C, O'Connor, RE, De Vivo, M, Doran, SD, Fisher, EL, Jenkinson, S, Karanian, D, Kormos, BL, Sharma, R, Walker, GS, Wright, AS, Yang, EX, Brodney, MA, Wager, TT, Verhoest, PR & Obach, RS 2018, 'Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189', ACS Medicinal Chemistry Letters, vol. 9, no. 2, pp. 68-72. https://doi.org/10.1021/acsmedchemlett.7b00343

TY - JOUR

T1 - Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189

AU - Stepan, Antonia F.

AU - Tran, Tuan P.

AU - Helal, Christopher J.

AU - Brown, Maria S.

AU - Chang, Cheng

AU - O'Connor, Rebecca E.

AU - De Vivo, Michael

AU - Doran, Shawn D.

AU - Fisher, Ethan L.

AU - Jenkinson, Stephen

AU - Karanian, David

AU - Kormos, Bethany L.

AU - Sharma, Raman

AU - Walker, Gregory S.

AU - Wright, Ann S.

AU - Yang, Edward X.

AU - Brodney, Michael A.

AU - Wager, Travis T.

AU - Verhoest, Patrick R.

AU - Obach, R. Scott

PY - 2018/2/8

Y1 - 2018/2/8

N2 - Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.

AB - Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.

KW - PDE2

KW - drug-drug interactions

KW - late-stage oxidation

KW - liver microsomes

KW - renal clearance

UR - https://www.scopus.com/pages/publications/85042034484

U2 - 10.1021/acsmedchemlett.7b00343

DO - 10.1021/acsmedchemlett.7b00343

M3 - Article

AN - SCOPUS:85042034484

SN - 1948-5875

VL - 9

SP - 68

EP - 72

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 2

ER -

Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189

Abstract

Keywords

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