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OBJECTIVE To develop a rapid, easy and clinically relevant in vivo model to evaluate novel insulin secretagogues on human islets, we investigated the effect of insulin secretagogues on functional human islets in a humanized mouse model. MATERIALS/METHODS Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice(More)
Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and(More)
Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these compounds was(More)
As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.
Glucagon-like peptide-1 (GLP-1) is a short peptide that can significantly reduce blood glucose level. Recombination oral long-acting glucagon-like peptide-1 (rolGLP-1), is a GLP-1 analog generated from site-specific mutation of GLP-1. CTB is a non-toxic portion of the cholera toxin and an ideal protein antigen carrier. In this study, we firstly constructed(More)
Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) have a similar but complementary role in regulating blood glucose level. This study was aimed to develop a functional-complementary dual insulinotropic peptide which releases both GLP-1 and GIP in vivo, and to investigate its therapeutic effect on type 2 diabetes in mice. We firstly(More)
Glucagon-like peptide-1 (GLP-1) reduces blood glucose and improves abnormal metabolism caused by hyperglycemia. The formation of thrombus, one of major consequences suffered from diabetes, can be inhibited by the treatment of Hirudin (HV). This study was aimed to develop a fusion peptide which combines functions of GLP-1 and HV to treat diabetes and its(More)
GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and(More)
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