title: Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.
abstract: The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle.
authors.affiliation: Deparment of Chemistry, The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA. repple@gnf.org
authors.forename: Robert
authors.initials: R
authors.lastname: Epple
authors.forename: Christopher
authors.initials: C
authors.lastname: Cow
authors.forename: Yongping
authors.initials: Y
authors.lastname: Xie
authors.forename: Mihai
authors.initials: M
authors.lastname: Azimioara
authors.forename: Ross
authors.initials: R
authors.lastname: Russo
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Vân T B
authors.initials: VT
authors.lastname: Nguyêñ-Trân
authors.forename: Cara
authors.initials: C
authors.lastname: Cuc Ngo
authors.forename: David
authors.initials: D
authors.lastname: Huang
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
authors.forename: Tracy
authors.initials: T
authors.lastname: Spalding
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerken
authors.forename: Maya
authors.initials: M
authors.lastname: Iskandar
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.forename: Shin-Shay
authors.initials: SS
authors.lastname: Tian
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D031541:Fluorescence Resonance Energy Transfer; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010080:Oxazoles; D047494:PPAR delta; D013844:Thiazoles