We first set out to identify
We first set out to identify the minimum pharmacophore. Early structure activity relationships (SAR) indicated that the chloro substituents were not required and that the benzisoxazole moiety could be replaced by a number of other groups. A broad survey of “left-hand” hydrophobic moieties was conducted (). Analogs of compound were synthesized as shown in , where borylated phenols are alkylated with the 8-pCPT-2-O-Me-cAMP-AM australia side chain and a subsequent Suzuki coupling under basic conditions (with ester hydrolysis) afforded final compounds . The benzoisoxazole “left-hand” piece was replaced with various heterocycles and substituted phenyl groups. Incorporation of 3-phenoxy phenyl () led to improved GPR120 potency while maintaining GPR40 selectivity. In general, substitution with various alkoxy groups (R) improved GPR120 potency. Compound , containing 2,5-disubstitution, further enhanced GPR120 potency. Various mono- and disubstitution patterns were evaluated, and the 2,5 disubstitution pattern proved optimal. Further optimization of 2,5-disubstitution was therefore attempted. Replacement of the 2-chloro with a fluoro substituent is tolerated ( and ), while the 5-trifluoromethoxyl moiety could be replaced with several alkoxy groups to yield compounds with similar GPR120 potency (, , , , ). Having demonstrated that a “left-hand” 2-chloro, 5-trifluoromethoxy aryl moiety provided favorable GPR120 functional activity, we turned our attention to the phenyl core (). To test whether substitution on the central core could restrict the flexibility of the butanoic acid chain and enforce an active conformation, various mono- and disubstituted analogs were synthesized. We found that 2,6-dimethyl substitution () maintained GPR120 potency and a favorable rodent pharmacokinetic profile () while improving selectivity over GPR40 activation. Several core modifications were attempted, and 2,6-disubstitution appeared to be optimal. Having demonstrated that ortho substitution of the phenyl core enhanced potency and selectivity, we explored conformationally constrained designs, wherein the ortho substituent was linked to the acid side chain to generate a benzofuran core. The synthetic scheme for benzofurans is shown in . 5-Chloro-2-hydroxybenzaldehyde () was alkylated with bromoacetylaldehyde diethyl acetal to form , which was then cyclized to form benzofuran aldehyde intermediate . A subsequent Horner-Wadsworth-Emmons reaction followed by hydrogenation gave benzofuran propanoic ester intermediate . Subsequent Suzuki coupling and hydrolysis afforded final compounds (). Compound , which maintained GPR120 potency and GPR40 selectivity, validated the constrained design working hypothesis and afforded a novel benzofuran series (). As ortho substitution had been shown to be beneficial in the acyclic series, an aryl substituent was incorporated adjacent to the benzofuran oxygen. Although flouro substitution demonstrated similar GPR120 potency, larger groups such as chloro, methyl and methoxy led to reduced potencies (data not shown). Compounds with 3,5-disubstitution also showed good GPR120 potency ( and ). We further demonstrated that reduction of the benzofuran to provide dihydrobenzofurans and resulted in comparable potencies and selectivities () compared to . We sought to further explore the benzofuran series by modifying the acid chain, such as shortening the chain and introducing tetrazoles with varying chain lengths. These changes were not well tolerated. However, methyl substituents along the alkyl chain ( and ) maintained similar potency (). Key analogs (, and ) from various sub-series were selected for further characterization, and these results are summarized in . Ancillary activities against both cardiac ion channels and the major cytochrome P450 enzymes were acceptable for compounds and , with compound exhibiting relatively potent inhibition of CYP3A4. Additionally, these compounds displayed favorable mouse pharmacokinetic (PK) profiles, characterized by low plasma clearance, moderate half-lives, and good oral bioavailability.