Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species

Kevin W. Hunt, Adam W. Cook, Ryan J. Watts, Christopher T. Clark, Guy Vigers, Darin Smith, Andrew T. Metcalf, Indrani W. Gunawardana, Michael Burkard, April A. Cox, Mary K. Geck Do, Darrin Dutcher, Allen A. Thomas, Sumeet Rana, Nicholas C. Kallan, Robert K. Delisle, James P. Rizzi, Kelly Regal, Douglas Sammond, Robert GronebergMichael Siu, Hans Purkey, Joseph P. Lyssikatos, Allison Marlow, Xingrong Liu, Tony P. Tang

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.

Original languageEnglish (US)
Pages (from-to)3379-3403
Number of pages25
JournalJournal of Medicinal Chemistry
Volume56
Issue number8
DOIs
StatePublished - Apr 25 2013

Fingerprint

Amyloid beta-Protein Precursor
Amyloid
Cerebrospinal Fluid
Alzheimer Disease
Brain
Enzymes
Amyloid Precursor Protein Secretases
Cathepsin D
Structure-Activity Relationship
Viperidae
Blood-Brain Barrier
Haplorhini
Rodentia
Guinea Pigs
Molecular Weight
Amino Acids
Peptides
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors : From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species. / Hunt, Kevin W.; Cook, Adam W.; Watts, Ryan J.; Clark, Christopher T.; Vigers, Guy; Smith, Darin; Metcalf, Andrew T.; Gunawardana, Indrani W.; Burkard, Michael; Cox, April A.; Geck Do, Mary K.; Dutcher, Darrin; Thomas, Allen A.; Rana, Sumeet; Kallan, Nicholas C.; Delisle, Robert K.; Rizzi, James P.; Regal, Kelly; Sammond, Douglas; Groneberg, Robert; Siu, Michael; Purkey, Hans; Lyssikatos, Joseph P.; Marlow, Allison; Liu, Xingrong; Tang, Tony P.

In: Journal of Medicinal Chemistry, Vol. 56, No. 8, 25.04.2013, p. 3379-3403.

Research output: Contribution to journalArticle

Hunt, KW, Cook, AW, Watts, RJ, Clark, CT, Vigers, G, Smith, D, Metcalf, AT, Gunawardana, IW, Burkard, M, Cox, AA, Geck Do, MK, Dutcher, D, Thomas, AA, Rana, S, Kallan, NC, Delisle, RK, Rizzi, JP, Regal, K, Sammond, D, Groneberg, R, Siu, M, Purkey, H, Lyssikatos, JP, Marlow, A, Liu, X & Tang, TP 2013, 'Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species', Journal of Medicinal Chemistry, vol. 56, no. 8, pp. 3379-3403. https://doi.org/10.1021/jm4002154
Hunt, Kevin W. ; Cook, Adam W. ; Watts, Ryan J. ; Clark, Christopher T. ; Vigers, Guy ; Smith, Darin ; Metcalf, Andrew T. ; Gunawardana, Indrani W. ; Burkard, Michael ; Cox, April A. ; Geck Do, Mary K. ; Dutcher, Darrin ; Thomas, Allen A. ; Rana, Sumeet ; Kallan, Nicholas C. ; Delisle, Robert K. ; Rizzi, James P. ; Regal, Kelly ; Sammond, Douglas ; Groneberg, Robert ; Siu, Michael ; Purkey, Hans ; Lyssikatos, Joseph P. ; Marlow, Allison ; Liu, Xingrong ; Tang, Tony P. / Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors : From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 8. pp. 3379-3403.
@article{3fa57488b0f24670938c57b37eea59a5,
title = "Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species",
abstract = "A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.",
author = "Hunt, {Kevin W.} and Cook, {Adam W.} and Watts, {Ryan J.} and Clark, {Christopher T.} and Guy Vigers and Darin Smith and Metcalf, {Andrew T.} and Gunawardana, {Indrani W.} and Michael Burkard and Cox, {April A.} and {Geck Do}, {Mary K.} and Darrin Dutcher and Thomas, {Allen A.} and Sumeet Rana and Kallan, {Nicholas C.} and Delisle, {Robert K.} and Rizzi, {James P.} and Kelly Regal and Douglas Sammond and Robert Groneberg and Michael Siu and Hans Purkey and Lyssikatos, {Joseph P.} and Allison Marlow and Xingrong Liu and Tang, {Tony P.}",
year = "2013",
month = "4",
day = "25",
doi = "10.1021/jm4002154",
language = "English (US)",
volume = "56",
pages = "3379--3403",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors

T2 - From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species

AU - Hunt, Kevin W.

AU - Cook, Adam W.

AU - Watts, Ryan J.

AU - Clark, Christopher T.

AU - Vigers, Guy

AU - Smith, Darin

AU - Metcalf, Andrew T.

AU - Gunawardana, Indrani W.

AU - Burkard, Michael

AU - Cox, April A.

AU - Geck Do, Mary K.

AU - Dutcher, Darrin

AU - Thomas, Allen A.

AU - Rana, Sumeet

AU - Kallan, Nicholas C.

AU - Delisle, Robert K.

AU - Rizzi, James P.

AU - Regal, Kelly

AU - Sammond, Douglas

AU - Groneberg, Robert

AU - Siu, Michael

AU - Purkey, Hans

AU - Lyssikatos, Joseph P.

AU - Marlow, Allison

AU - Liu, Xingrong

AU - Tang, Tony P.

PY - 2013/4/25

Y1 - 2013/4/25

N2 - A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.

AB - A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.

UR - http://www.scopus.com/inward/record.url?scp=84876854153&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876854153&partnerID=8YFLogxK

U2 - 10.1021/jm4002154

DO - 10.1021/jm4002154

M3 - Article

C2 - 23537249

AN - SCOPUS:84876854153

VL - 56

SP - 3379

EP - 3403

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -