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Highly selective peroxisome proliferator-activated receptor Î´ (PPARÎ´) modulator demonstrates improved safety profile compared to GW501516.

Lagu, Bharat; Kluge, Arthur F; Goddeeris, Matthew M; Tozzo, Effie; Fredenburg, Ross A; Chellur, Shekar; Senaiar, Ramesh S; Jaleel, Mahaboobi; Babu, D Ravi Krishna; Tiwari, Nirbhay K; Takahashi, Taisuke; Patane, Michael A.

Bioorg Med Chem Lett ; 28(3): 533-536, 2018 02 01.

Article in English | MEDLINE | ID: mdl-29275935

ABSTRACT

Compound 1 regulates significantly fewer genes than the PPARÎ´ modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns.

Subject(s)

PPAR delta/metabolism , Thiazoles/pharmacology , Animals , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Rats , Structure-Activity Relationship

Novel highly selective peroxisome proliferator-activated receptor Î´ (PPARÎ´) modulators with pharmacokinetic properties suitable for once-daily oral dosing.

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

Bioorg Med Chem Lett ; 27(23): 5230-5234, 2017 12 01.

Article in English | MEDLINE | ID: mdl-29103972

ABSTRACT

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

Subject(s)

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

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