Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 11, 2009, Pages 2969-2973

  Bass, Jonathan Y ^a   Caldwell, Richard D ^a   Caravella, Justin A ^a   Chen, Lihong ^a   Creech, Katrina L ^a   Deaton, David N ^a   Madauss, Kevin P ^a   Marr, Harry B ^a   McFadyen, Robert B ^a   Miller, Aaron B ^a   Parks, Derek J ^a   Todd, Dan ^a   Williams, Shawn P ^a   Wisely, G Bruce ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

Bile acid receptor; Farnesoid X receptor agonist; FXR; FXR X ray co crystal structure; GW4064; NR1H4; Nuclear receptor modulator

Indexed keywords

3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID; FARNESOID X RECEPTOR; ISOXAZOLE DERIVATIVE; PHENOL;

ARTICLE; DRUG DISTRIBUTION; DRUG POTENCY; DRUG SYNTHESIS; FLUORESCENCE RESONANCE ENERGY TRANSFER; STRUCTURE ACTIVITY RELATION;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; FLUORESCENCE RESONANCE ENERGY TRANSFER; ISOXAZOLES; RATS; RECEPTORS, CYTOPLASMIC AND NUCLEAR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 65149087208     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.04.047     Document Type: Article

References (20)

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14. The alcohol 2h was prepared from commercially available (E)-2,6-dichlorocinnamic acid in three synthetic steps. First, the acid was esterified employing the Fischer method with catalytic sulfuric acid in methanol (94% yield). Then, the resulting unsaturated methyl ester was converted to the methyl 2-(2,6-dichlorophenyl)cyclopropanecarboxylate via its addition to the in situ generated sulfur ylide prepared by adding sodium hydride to trimethylsulfoxonium iodide in dimethyl sulfoxide (26% yield). Finally, reduction of the ester with di-iso-butylaluminum hydride in tetrahydrofuran afforded the desired [2-(2,6-dichlorophenyl)cyclopropyl]methanol 2h (78% yield).
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18. Mitsunobu reactions in this Letter were performed under the following conditions: a mixture of 1.0 equiv each of the alcohol, the phenol, di-iso-propyl diazodicarboxylate, and triphenylphosphine were placed in a microwave reaction vessel and toluene was added to make a 0.1 M mixture. Then, the vessel was sealed and heated in a microwave reactor between 85 and 100 °C for between 600 and 1000 s. The resulting mixture was then concentrated and the residue was purified by silica gel chromatography with gradients of ethyl acetate in hexanes.
19. Saponification reactions in this Letter were performed under the following conditions: The ester was placed in a microwave reaction vessel and a 2:1 mixture of tetrahydrofuran and methanol was added, followed by 1.5 equiv of 1 M sodium hydroxide. Then, the vessel was sealed and heated in a microwave reactor between 100 and 120 °C for 500 s. The resulting mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated.
20. The stereoisomers of the sec-butyl group were separated at the alcohol 6l stage and carried through the rest of the synthesis separately to give analogs 1am and 1an.