PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Pyrrolo[2,3‑c]pyridines as Imaging Agents for Neurofibrilary Tangles Benjamin Blass* Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, United States Title:
Pyrrolo[2,3-c]pyridines as imaging agents for neurofibrilary tangles
Patent Application Number: WO 2015188368 A2 Priority Application: PCT/CN2014/079834
Publication date: Priority date:
December 17th, 2015 June 13th, 2014
Inventors:
Abbas, Walji; Hostetler, Eric; Greshock, Thomas; Li, Jing; Moore, Keith P.; Bennacef, Idriss; Mulhearn, James; Selnick, Harold;
Assignee Company:
Merck, Sharpe and Dohme, Inc.
Disease Area:
CNS Alzheimer’s disease
Summary:
Alzheimer’s disease (AD), a neurodegenerative disorder characterized by neuronal and synaptic loss, brain atrophy, and slow,
Wang, Yaode; Yang, Kun; Fu, Jianmin Biological Target:
Tau protein and tau aggregates
progressive dementia first characterized by Dr. Alois Alzheimer in 1901, remains a major unmet medical need. Despite decades of research, a cure remains elusive and treatment options are limited. In 2015, approximately 5.3 million US citizens had Alzheimer’s disease, and the direct cost of AD patient care in the US was ∼$226 billion. In the absence of novel therapies, the US AD patient population is expected to exceed 13.8 million by 2050, and the cost of care will balloon to over $1.1 trillion. Although the pathogenesis of AD has not been determined, there are two major theories that describe its pathogenesis, the amyloid hypothesis and the tau theory. According to the amyloid hypothesis the neurodegeneration and loss of cognitive function associated with AD are caused by the buildup of β-amyloid plaques. These plaques are believed to be the result of improper amyloid precursor protein (APP) processing by β-secretase (BACE) and γ-secretase, which leads to a buildup of the Aβ-42 fragment of APP. Aβ-42 is prone to aggregation and plaque formation, and it has been hypothesized that preventing the formation and/or clearing these materials from the brain will arrest AD progression. The tau theory, however, hypothesizes that AD pathogenesis is caused by mishandling of tubulin-associated unit (tau) proteins. Under normal conditions, this highly soluble microtubule associated protein modulates the stability of axonal microtubules. In AD patients, however, tau becomes hyperphosphorylated, which substantially decreases its solubility. This leads to the formation of tau aggregates and neurofibrillary tangles inside nerve cells. This, in turn, causes neuron death, cognitive impairment, and other symptoms of AD. Diagnostic tools capable of detecting the presence of either β-amyloid plaques or tau aggregates could provide a method of diagnosing AD. The present disclosure describes a series of pyrrolo[2,3-c]pyridines useful as positron emission tomography (PET) imaging agents capable of binding to tau aggregates. Important Compound Classes:
Received:
r XXXX American Chemical Society
A
February 20, 2016
dx.doi.org/10.1021/acsmedchemlett.6b00078 | ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters Definitions:
PATENT HIGHLIGHT
X represents CH, or N; C1 6alkyl, said alkyl optionally substituted with 1 to 3 groups of Ra:
R represents hydrogen, or 1
R represents hydrogen,
C1 6alkyl,
C1 R2 represents O(CH2)nhalogen,
alkyl, OC1 6 alkyl, C2 6 alkenyIR3, C2 6 alkynyIR3, (CH2)nOR, (CH2)nhalogen, C6 10 aryl, C5 10 heterocyclyl, N(R)2, O(CH2)nRa, N(CH3)(CH2)nOR, NRC(O)R,
NH(CH2)nhalo,
6
NC(O)C6
10
CN,
aryl,
(CH2)nNH(CH2)nN(R)2,
NC(O)C5
10
heterocyclyl,
C2 6alkenyl,
(CH2)nOR, or
N(CH3) (CH2)nhalogen,
(CH2)nhalogen;
C(O)NC6
10
aryl, said
alkyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra; or an adjacent R1 can combine with R2 to form a nine- to 10-membered bicyclic ring together with the ring to which R1 and R2 are attached, said bicyclic ring optionally interrupted with N, S, and/or O, said ring optionally substituted with 1 to 3 groups of Ra; R
3
represents C5
hydrogen,
10heteroaryl,
C1 6alkyl,
(CH2)nhalogen,
(CH2)nN(R)2,
(CH2)nNR(CH2)nN(R)2,
C6
10aryl,
said alkyl, aryl, and heteroaryl optionally substituted with 1 to 3 group of Ra;
Ra represents CN, CF3, Cl‑6alkyl, C2 6alkenyl, C2 6alkynyl, C6 10aryl, C5 10 heterocyclyl, CN, NO2, (CH2)nhalogen, O(CH2)nhalogen, (CH2)nOR, O(CH2)nC6 10 aryl, (CH2)nN(R)2, C(O)N(R)2, N(CH3) (CH2)nOR, NRCOR, COR,
NH(CH2)nhalo,
NC(O)C C6
10aryl,
N(CH3) (CH2)nhalogen, C(O)C6
10
aryl, or
CO2R;
Rb represents -C1 6alkyl, -OR, or halogen; and n represents 0 4. Key Structures:
Recent Review Articles:
1. Anand, K.; Sabbagh, M. Early investigational drugs targeting tau protein for the treatment of Alzheimer’s disease. Expert Opin. Invest. Drugs 2015, 24 (10), 1355 1360. 2. Oukoloff, K.; Cieslikiewicz-Bouet, M.; Chao, S.; Da Costa Branquinho, E.; Bouteiller, C.; Jean, L.; Renard, P.-Y. PET and SPECT Radiotracers for Alzheimer’s Disease. Curr. Med. Chem. 2015, 22 (28), 3278 3304. 3. Huang, Y.; Wu, Z.; Zhou, B. Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity. Cell. Mol. Life Sci. 2016, 73 (1), 1 21. 4. Patel, V.; Zhang, X.; Tautiva, N. A.; Nyabera, A. N.; Owa, O. O.; Baidya, M.; Sung, H. C.; Taunk, P. S.; Abdollahi, S.; Charles, S.; Gonnella, R. A.; Gadi, N.; Duong, K. T.; Fawver, J. N.; Ran, C.; Jalonen, T. O.; Murray, I. V. J. Small Molecules and Alzheimer’s Disease: Misfolding, Metabolism and Imaging. Curr. Alzheimer Res. 2015, 12 (5), 445 461.
Biological Assay:
Tau binding assay using human brain samples. Amyloid binding assay using human brain samples.
B
dx.doi.org/10.1021/acsmedchemlett.6b00078 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
Biological Data:
Claims:
27 total claims 21 composition of matter claims 6 method of use claims
’ AUTHOR INFORMATION Corresponding Author
*Tel: 215-707-1085. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/acsmedchemlett.6b00078 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
