Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice.
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 brain-penetrant 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.
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Kurt
K
Giles
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
David B
DB
Berry
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Carlo
C
Condello
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Brittany N
BN
Dugger
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Zhe
Z
Li
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Abby
A
Oehler
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Sumita
S
Bhardwaj
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Manuel
M
Elepano
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Shenheng
S
Guan
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
B Michael
BM
Silber
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California.
Steven H
SH
Olson
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California stanley.prusiner@ucsf.edu.
Stanley B
SB
Prusiner
D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D007562:Creutzfeldt-Jakob Syndrome / Q000188:drug therapy; D055808:Drug Discovery; D005260:Female; D051379:Mice; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship; D016019:Survival Analysis
D000577:Amides