Abstract
Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self- Templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high- Throughput screening hits with the aryl amide scaffold and explored the structure- Activity relationships around three series differing in their N- Aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brainpenetrant leads from each series, together with a related N- Aryl piperazine lead, were escalated to long- Term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2- Aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 537-547 |
| Number of pages | 11 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 358 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 1 2016 |
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ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology
Cite this
Optimization of aryl amides that extend survival in prion-infected mice. / Giles, Kurt; Berry, David B.; Condello, Carlo; Dugger, Brittany; Li, Zhe; Oehler, Abby; Bhardwaj, Sumita; Elepano, Manuel; Guan, Shenheng; Silber, B. Michael; Olson, Steven H.; Prusiner, Stanley B.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 358, No. 3, 01.09.2016, p. 537-547.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Optimization of aryl amides that extend survival in prion-infected mice
AU - Giles, Kurt
AU - Berry, David B.
AU - Condello, Carlo
AU - Dugger, Brittany
AU - Li, Zhe
AU - Oehler, Abby
AU - Bhardwaj, Sumita
AU - Elepano, Manuel
AU - Guan, Shenheng
AU - Silber, B. Michael
AU - Olson, Steven H.
AU - Prusiner, Stanley B.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self- Templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high- Throughput screening hits with the aryl amide scaffold and explored the structure- Activity relationships around three series differing in their N- Aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brainpenetrant leads from each series, together with a related N- Aryl piperazine lead, were escalated to long- Term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2- Aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.
AB - Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self- Templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high- Throughput screening hits with the aryl amide scaffold and explored the structure- Activity relationships around three series differing in their N- Aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brainpenetrant leads from each series, together with a related N- Aryl piperazine lead, were escalated to long- Term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2- Aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.
UR - http://www.scopus.com/inward/record.url?scp=84983735453&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983735453&partnerID=8YFLogxK
U2 - 10.1124/jpet.116.235556
DO - 10.1124/jpet.116.235556
M3 - Article
C2 - 27317802
AN - SCOPUS:84983735453
VL - 358
SP - 537
EP - 547
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -