Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771)

Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7

Nigel A. Swain, Dave Batchelor, Serge Beaudoin, Bruce M. Bechle, Paul A. Bradley, Alan D. Brown, Bruce Brown, Ken J. Butcher, Richard P. Butt, Mark L. Chapman, Stephen Denton, David Ellis, Sebastien R.G. Galan, Steven M. Gaulier, Ben S. Greener, Marcel J. De Groot, Mel S. Glossop, Ian K. Gurrell, Jo Hannam, Matthew S. Johnson & 14 others Zhixin Lin, Christopher J. Markworth, Brian E. Marron, David S. Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff, David J. Rawson, Sarah J. Ransley, Steven M. Reister, Kosuke Sasaki, R. Ian Storer, Paul A. Stupple, Christopher W. West

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)

Abstract

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

Original languageEnglish
Pages (from-to)7029-7042
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number16
DOIs
Publication statusPublished - 24 Aug 2017
Externally publishedYes

Cite this

Swain, Nigel A. ; Batchelor, Dave ; Beaudoin, Serge ; Bechle, Bruce M. ; Bradley, Paul A. ; Brown, Alan D. ; Brown, Bruce ; Butcher, Ken J. ; Butt, Richard P. ; Chapman, Mark L. ; Denton, Stephen ; Ellis, David ; Galan, Sebastien R.G. ; Gaulier, Steven M. ; Greener, Ben S. ; De Groot, Marcel J. ; Glossop, Mel S. ; Gurrell, Ian K. ; Hannam, Jo ; Johnson, Matthew S. ; Lin, Zhixin ; Markworth, Christopher J. ; Marron, Brian E. ; Millan, David S. ; Nakagawa, Shoko ; Pike, Andy ; Printzenhoff, David ; Rawson, David J. ; Ransley, Sarah J. ; Reister, Steven M. ; Sasaki, Kosuke ; Storer, R. Ian ; Stupple, Paul A. ; West, Christopher W. / Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771) : Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 16. pp. 7029-7042.
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title = "Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7",
abstract = "A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.",
author = "Swain, {Nigel A.} and Dave Batchelor and Serge Beaudoin and Bechle, {Bruce M.} and Bradley, {Paul A.} and Brown, {Alan D.} and Bruce Brown and Butcher, {Ken J.} and Butt, {Richard P.} and Chapman, {Mark L.} and Stephen Denton and David Ellis and Galan, {Sebastien R.G.} and Gaulier, {Steven M.} and Greener, {Ben S.} and {De Groot}, {Marcel J.} and Glossop, {Mel S.} and Gurrell, {Ian K.} and Jo Hannam and Johnson, {Matthew S.} and Zhixin Lin and Markworth, {Christopher J.} and Marron, {Brian E.} and Millan, {David S.} and Shoko Nakagawa and Andy Pike and David Printzenhoff and Rawson, {David J.} and Ransley, {Sarah J.} and Reister, {Steven M.} and Kosuke Sasaki and Storer, {R. Ian} and Stupple, {Paul A.} and West, {Christopher W.}",
year = "2017",
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doi = "10.1021/acs.jmedchem.7b00598",
language = "English",
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Swain, NA, Batchelor, D, Beaudoin, S, Bechle, BM, Bradley, PA, Brown, AD, Brown, B, Butcher, KJ, Butt, RP, Chapman, ML, Denton, S, Ellis, D, Galan, SRG, Gaulier, SM, Greener, BS, De Groot, MJ, Glossop, MS, Gurrell, IK, Hannam, J, Johnson, MS, Lin, Z, Markworth, CJ, Marron, BE, Millan, DS, Nakagawa, S, Pike, A, Printzenhoff, D, Rawson, DJ, Ransley, SJ, Reister, SM, Sasaki, K, Storer, RI, Stupple, PA & West, CW 2017, 'Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7', Journal of Medicinal Chemistry, vol. 60, no. 16, pp. 7029-7042. https://doi.org/10.1021/acs.jmedchem.7b00598

Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771) : Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7. / Swain, Nigel A.; Batchelor, Dave; Beaudoin, Serge; Bechle, Bruce M.; Bradley, Paul A.; Brown, Alan D.; Brown, Bruce; Butcher, Ken J.; Butt, Richard P.; Chapman, Mark L.; Denton, Stephen; Ellis, David; Galan, Sebastien R.G.; Gaulier, Steven M.; Greener, Ben S.; De Groot, Marcel J.; Glossop, Mel S.; Gurrell, Ian K.; Hannam, Jo; Johnson, Matthew S.; Lin, Zhixin; Markworth, Christopher J.; Marron, Brian E.; Millan, David S.; Nakagawa, Shoko; Pike, Andy; Printzenhoff, David; Rawson, David J.; Ransley, Sarah J.; Reister, Steven M.; Sasaki, Kosuke; Storer, R. Ian; Stupple, Paul A.; West, Christopher W.

In: Journal of Medicinal Chemistry, Vol. 60, No. 16, 24.08.2017, p. 7029-7042.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771)

T2 - Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7

AU - Swain, Nigel A.

AU - Batchelor, Dave

AU - Beaudoin, Serge

AU - Bechle, Bruce M.

AU - Bradley, Paul A.

AU - Brown, Alan D.

AU - Brown, Bruce

AU - Butcher, Ken J.

AU - Butt, Richard P.

AU - Chapman, Mark L.

AU - Denton, Stephen

AU - Ellis, David

AU - Galan, Sebastien R.G.

AU - Gaulier, Steven M.

AU - Greener, Ben S.

AU - De Groot, Marcel J.

AU - Glossop, Mel S.

AU - Gurrell, Ian K.

AU - Hannam, Jo

AU - Johnson, Matthew S.

AU - Lin, Zhixin

AU - Markworth, Christopher J.

AU - Marron, Brian E.

AU - Millan, David S.

AU - Nakagawa, Shoko

AU - Pike, Andy

AU - Printzenhoff, David

AU - Rawson, David J.

AU - Ransley, Sarah J.

AU - Reister, Steven M.

AU - Sasaki, Kosuke

AU - Storer, R. Ian

AU - Stupple, Paul A.

AU - West, Christopher W.

PY - 2017/8/24

Y1 - 2017/8/24

N2 - A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

AB - A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

UR - http://www.scopus.com/inward/record.url?scp=85028584771&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.7b00598

DO - 10.1021/acs.jmedchem.7b00598

M3 - Article

VL - 60

SP - 7029

EP - 7042

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 16

ER -