Dataset Information

Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.

ABSTRACT: The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ? 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels.

SUBMITTER: Peukert S

PROVIDER: S-EPMC4190643 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.

Peukert Stefan S Hughes Richard R Nunez Jill J He Guo G Yan Zhao Z Jain Rishi R Llamas Luis L Luchansky Sarah S Carlson Adam A Liang Guiqing G Kunjathoor Vidya V Pietropaolo Mike M Shapiro Jeffrey J Castellana Anja A Wu Xiaoping X Bose Avirup A

ACS medicinal chemistry letters 20140804 10

The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) ...[more]

PMID: 25313322

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Project description:Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 ?M. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.

Dataset Information

Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.

Publications

Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.

Similar Datasets

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