Novel highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulators with pharmacokinetic properties suitable for once-daily oral dosing

Bharat Lagu; Arthur F Kluge; Ross A Fredenburg; Effie Tozzo; Ramesh S Senaiar; Mahaboobi Jaleel; Sunil K Panigrahi; Nirbhay K Tiwari; Narasimha R Krishnamurthy; Taisuke Takahashi; Michael A Patane

doi:10.1016/j.bmcl.2017.10.037

Novel highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulators with pharmacokinetic properties suitable for once-daily oral dosing

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5230-5234. doi: 10.1016/j.bmcl.2017.10.037. Epub 2017 Oct 27.

Affiliations

¹ Mitobridge, Inc., 1030 Massachusetts Ave., Cambridge, MA 02138, United States. Electronic address: blagu@mitobridge.com.
² Mitobridge, Inc., 1030 Massachusetts Ave., Cambridge, MA 02138, United States.
³ Aurigene Discovery Technologies, Ltd., Hyderabad and Bengaluru, India.
⁴ Astellas Pharma, Tsukuba, Japan.

PMID: 29103972
DOI: 10.1016/j.bmcl.2017.10.037

Abstract

Optimization of benzamide PPARδ modulator 1 led to (E)-6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)-4-methylhex-4-enoic acid (18), a potent selective PPARδ modulator with significantly improved exposure in multiple species following oral administration.

Keywords: GW501516; Ligand binding domain; PPARδ modulator; Plasma exposure; X-ray structure.

MeSH terms

Administration, Oral
Animals
Benzamides / administration & dosage
Benzamides / blood
Benzamides / pharmacokinetics*
Dose-Response Relationship, Drug
Humans
Injections, Intravenous
Macaca fascicularis
Male
Mice
Molecular Structure
Rats, Wistar
Structure-Activity Relationship

Substances

Benzamides