- Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes
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GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound 4 suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound 20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with 20e is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.
- Guo, Liangqin,Parker, Dann L.,Zang, Yi,Sweis, Ramzi F.,Liu, Weiguo,Sherer, Edward C.,Buist, Nicole,Terebetski, Jenna,Kelly, Terri,Bugianesi, Randal,Priest, Birgit T.,Dingley, Karen H.,Li, Xiaofang,Mitelman, Stan,Salituro, Gino,Trujillo, Maria E.,Pachanski, Michele,Kirkland, Melissa,Powles, Mary Ann,Eiermann, George J.,Feng, Yue,Shang, Jin,Howard, Andrew D.,Ujjainwalla, Feroze,Sinz, Christopher J.,Debenham, John S.,Edmondson, Scott D.,Nargund, Ravi P.,Hagmann, William K.,Li, Derun
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p. 1107 - 1111
(2016/12/16)
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- Imidazole lipoxygenase inhibitors
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Certain novel imidazole derivatives having the ability to inhibit the lipoxygenase enzyme and having formula (I), wherein Y is hydrogen, C1 -C8 alkyl, halosubstituted C1 -C4 alkyl, phenyl, substituted phenyl, C7 -C14 phenylalkyl, C7 -C14 (substituted phenyl)alkyl, pyridyl, substituted pyridyl, C6 -C13 pyridylalkyl or C6 -C13 (substituted pyridyl)alkyl, wherein each substituent is independently halo, nitro, cyano, C1 -C4 alkyl, C1 -C4 alkoxy, halosubstituted C1 -C4 alkyl, halosubstituted C1 -C4 alkoxy, NR4 R5, CO2 R4 or CONR4 R5, wherein R4 and R5 are each, independently, hydrogen or C1 -C6 alkyl; Ar1 and Ar2 are each, independently, phenylene, mono-substituted phenylene or di-substituted phenylene, wherein the substituents are, independently, halo, C1 -C4 alkyl, C1 -C4 alkoxy, halo-substituted C1 -C4 alkyl or halo-substituted C1 -C4 alkoxy; X and X1 are each, independently, O, S, SO or SO2 ; R' is hydrogen or C1 -C4 alkyl; and R2 and R3 are each, independently, methylene, ethylene or propylene. These compounds are useful for the treatment of disease states such as bronchial asthma, skin disorders and arthritis in mammals, and as the active ingredient in pharmaceutical compositions for treating such conditions.
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