Patent Highlight pubs.acs.org/acsmedchemlett
PPAR Agonists, Compounds, Pharmaceutical Compositions, and Methods of Use Thereof Benjamin Blass* Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, United States PPAR agonists, compounds, pharmaceutical compositions, and methods of use thereof WO2016057660 Publication date: April 14th, 2016 US62/061,430 Priority date: October 8th, 2014 Baiga, T.; Downes, M.; Evans, R.; Kluge, A.; Lagu, B.; Miura, M.; Panigrahi, S. K.; Patane, M.; Samajdar, S.; Senaiar, R.; Takahashi, T. Assignee Company: Mitobridge, Inc. and Salk Institute for Biological Studies Disease Area: Demyelinating and muscular diseases Biological Target: peroxisome proliferator-activated receptor δ (PPARδ) Summary: Peroxisome proliferator-activated receptors (PPAR) are a family of nuclear receptor proteins. Their primary function is to act as transcription factors that regulate gene expression. To date, three major subtypes have been identified, PPARα, PPARδ, and PPARγ. These proteins are key regulators of major metabolic pathways such as fatty acid oxidation, lipogenesis, and carbohydrate utilization. Functionally, PPARs form heterodimers with retinoic acid receptors (RXR), and these heterodimers interact with PPAR receptor elements (PPRE) in DNA to form active transcriptional complexes. PPARα is highly expressed in the liver where it plays a key role in regulating lipid metabolism. PPARγ, however, is found primarily in adipose tissues where it regulates adipogenesis and carbohydrate metabolism. Finally, PPARδ is widely expressed and has been detected in many areas of the body including the small intestine, colon, heart, spleen, liver, skeletal muscle, thymus, lung, and brain. PPARδ’s major function is the regulation of lipid and glucose metabolism. It was recently discovered that mice that are PPARδ deficient exhibit abnormal neurophysiological processes. Specifically, these mice have substantially decreased myelination of nerve cells and increased inflammatory responses. These findings suggest that PPARδ modulation may be a viable approach to the treatment of demyelinating diseases such as multiple sclerosis. The present disclosure describes compounds capable of modulating PPARδ activity that are useful for the treatment of demyelinating and muscular diseases. Important Compound Classes: Title: Patent Application Number: Priority Application: Inventors:
Definitions:
Z is CH, N, or N−O; Ring A is optionally substituted phenylene when Z is CH, optionally substituted pyridinylene when Z is N, or optionally substituted N-oxide pyridinylene when Z is N−O; Ar is optionally substituted 5- or 6-membered monocyclic arylene or heteroarylene, provided that when Ar is 5-membered heteroarylene, R2 and −C(O)NR3− are oriented 1, 3 to each other on the ring, wherein position 1 is the point of attachment of Ar to the −C(O)NR3-; or Ar is optionally substituted 9- or 10-membered fused bicyclic heteroarylene; R1 is −OR1A or − NR1AR1B; R1A, R1B are each independently hydrogen or C1−C4-alkyl; W is O, and L is −(CH2)n−, wherein n is an integer between 1 and 6, and one or more (CH2) is replaced with −CH2−CH(CH3)−, −CH(CH3)−CH2−, −CH2−C(CH3)2−, −C(CH3)2−CH2−, −HCC(CH3)−, −(CH3)CCH−,
, −CH2−O−CH2−, −CH2−
S−CH2−, −CH2− CH(F)−, −CH(F)−CH2−, −CH2−CF2−, −CF2−CH2−, −CH2−C(O)−, −C(O)−CH2−, optionally substituted arylene, optionally substituted arylene ether, or optionally substituted heteroarylene; or W is CH2, CHCH, or CC, and L is −(CH2)n−, wherein n is an integer between 1 and 6, and one or more (CH2) is optionally replaced with −CH2−CH(CH3)−, −CH(CH3)−CH2−, CH2−C(CH3)2−, −C(CH3)2−CH2−, −HCC(CH3)−, − (CH3)CCH−,
,
−CH2−O−CH2−, −CH2−S−CH2−, −CH2−CH(F)−, −CH(F)−CH2−, −CH2−CF2−, −CF2−CH2−, −CH2−C(O)−, or −C(O)−CH2−; each R21 is independently hydrogen, halogen, or C1−C4-alkyl; R2 is halogen, C1−C4-alkyl, C3−C6-cycloalkyl, CN, C1−C4-alkoxy, C1−C4-haloalkoxy, SO2(C1−C4-alkyl), 5- or 6-membered heterocycloalkyl, , −O(CH2)mR2B, NH(C1−C4-alkyl), N(C1−C4-alkyl)z, C(O)(C1−C4-alkyl), optionally substituted aryl, or optionally substituted 5-membered heteroaryl; m is an integer having a value of 0, 1, 2, or 3; R2A and R2B are each independently C1−C4-alkyl, C3−C6-cycloalkyl, or C1−C4 haloalkyl; R3 is C1−C4-alkyl,
,
, or C1−C4-haloalkyl; and
each R4 is independently H, D, or F.
Received: August 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.6b00301 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Key Structures:
Recent Review Articles:
Biological Assay:
Bojic, L. A.; Huff, M. W. Peroxisome proliferator-activated receptor δ: a multifaceted metabolic player. Curr. Opin. Lipidol. 2013, 24 (2), 171−177. Lamers, C.; Schubert-Zsilavecz, M.; Merk, D. Therapeutic modulators of peroxisome proliferator-activated receptors (PPAR): a patent review (2008-present). Expert Opin. Ther. Patents 2012, 22 (7), 803−841. Kahremany, S.; Livne, A.; Gruzman, A.; Senderowitz, H.; Sasson, S. Activation of PPARδ: from computer modeling to biological effects. Br. J. Pharmacol. 2015, 172 (3), 754−770. PPARδ Transactivation Assay Nuclear Hormone Receptor (NHR) Assays
Biological Data:
Claims:
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49 total claims 37 composition of matter claims 12 method of use claims
AUTHOR INFORMATION
Corresponding Author
*Tel: 215-707-1085. E-mail:
[email protected]. Notes
The author declares no competing financial interest. B
DOI: 10.1021/acsmedchemlett.6b00301 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
