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

[Image: see text] 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 phy...

Descripción completa

Detalles Bibliográficos
Autores principales: Stepan, Antonia F., Tran, Tuan P., Helal, Christopher J., Brown, Maria S., Chang, Cheng, O’Connor, Rebecca E., De Vivo, Michael, Doran, Shawn D., Fisher, Ethan L., Jenkinson, Stephen, Karanian, David, Kormos, Bethany L., Sharma, Raman, Walker, Gregory S., Wright, Ann S., Yang, Edward X., Brodney, Michael A., Wager, Travis T., Verhoest, Patrick R., Obach, R. Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807869/
https://www.ncbi.nlm.nih.gov/pubmed/29456790
http://dx.doi.org/10.1021/acsmedchemlett.7b00343
_version_ 1783299361533329408
author Stepan, Antonia F.
Tran, Tuan P.
Helal, Christopher J.
Brown, Maria S.
Chang, Cheng
O’Connor, Rebecca E.
De Vivo, Michael
Doran, Shawn D.
Fisher, Ethan L.
Jenkinson, Stephen
Karanian, David
Kormos, Bethany L.
Sharma, Raman
Walker, Gregory S.
Wright, Ann S.
Yang, Edward X.
Brodney, Michael A.
Wager, Travis T.
Verhoest, Patrick R.
Obach, R. Scott
author_facet Stepan, Antonia F.
Tran, Tuan P.
Helal, Christopher J.
Brown, Maria S.
Chang, Cheng
O’Connor, Rebecca E.
De Vivo, Michael
Doran, Shawn D.
Fisher, Ethan L.
Jenkinson, Stephen
Karanian, David
Kormos, Bethany L.
Sharma, Raman
Walker, Gregory S.
Wright, Ann S.
Yang, Edward X.
Brodney, Michael A.
Wager, Travis T.
Verhoest, Patrick R.
Obach, R. Scott
author_sort Stepan, Antonia F.
collection PubMed
description [Image: see text] 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.
format Online
Article
Text
id pubmed-5807869
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-58078692018-02-16 Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189 Stepan, Antonia F. Tran, Tuan P. Helal, Christopher J. Brown, Maria S. Chang, Cheng O’Connor, Rebecca E. De Vivo, Michael Doran, Shawn D. Fisher, Ethan L. Jenkinson, Stephen Karanian, David Kormos, Bethany L. Sharma, Raman Walker, Gregory S. Wright, Ann S. Yang, Edward X. Brodney, Michael A. Wager, Travis T. Verhoest, Patrick R. Obach, R. Scott ACS Med Chem Lett [Image: see text] 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. American Chemical Society 2018-01-04 /pmc/articles/PMC5807869/ /pubmed/29456790 http://dx.doi.org/10.1021/acsmedchemlett.7b00343 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Stepan, Antonia F.
Tran, Tuan P.
Helal, Christopher J.
Brown, Maria S.
Chang, Cheng
O’Connor, Rebecca E.
De Vivo, Michael
Doran, Shawn D.
Fisher, Ethan L.
Jenkinson, Stephen
Karanian, David
Kormos, Bethany L.
Sharma, Raman
Walker, Gregory S.
Wright, Ann S.
Yang, Edward X.
Brodney, Michael A.
Wager, Travis T.
Verhoest, Patrick R.
Obach, R. Scott
Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
title Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
title_full Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
title_fullStr Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
title_full_unstemmed Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
title_short Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189
title_sort late-stage microsomal oxidation reduces drug–drug interaction and identifies phosphodiesterase 2a inhibitor pf-06815189
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807869/
https://www.ncbi.nlm.nih.gov/pubmed/29456790
http://dx.doi.org/10.1021/acsmedchemlett.7b00343
work_keys_str_mv AT stepanantoniaf latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT trantuanp latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT helalchristopherj latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT brownmarias latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT changcheng latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT oconnorrebeccae latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT devivomichael latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT doranshawnd latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT fisherethanl latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT jenkinsonstephen latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT karaniandavid latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT kormosbethanyl latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT sharmaraman latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT walkergregorys latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT wrightanns latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT yangedwardx latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT brodneymichaela latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT wagertravist latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT verhoestpatrickr latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189
AT obachrscott latestagemicrosomaloxidationreducesdrugdruginteractionandidentifiesphosphodiesterase2ainhibitorpf06815189

Ejemplares similares