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Discovery of MK-8282 as a Potent G-Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes
10.1021/acsmedchemlett.8b00073 2018-04-11 The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPC... |
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Academic Drug Development: The DRIVE Model
10.1021/acsmedchemlett.8b00124 2018-04-11 Although there are hundreds of academic drug discovery centers open around the world, there are comparatively few academic drug development centers that contain the key core competencies needed to progress a lead compound into clinical trials. This is largely... |
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SAR Studies of N-[2-(1H-Tetrazol-5-yl)phenyl]benzamide Derivatives as Potent G Protein-Coupled Receptor-35 Agonists
10.1021/acsmedchemlett.7b00510 2018-04-10 G protein-coupled receptor-35 (GPR35) has emerged as a potential target in the treatment of pain and inflammatory and metabolic diseases. We have discovered a series of potent GPR35 agonists based on a coumarin scaffold and found that the introduction of a 1H... |
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Structure–Activity Relationships of Radioiodinated Benzoimidazopyridine Derivatives for Detection of Tau Pathology
10.1021/acsmedchemlett.8b00092 2018-04-10 It is generally accepted that neurofibrillary tangles consisting of tau proteins are involved in the pathogenesis of Alzheimer’s disease (AD). For selective detection of tau pathology, we synthesized and evaluated radioiodinated benzoimidazopyridine (BIP) der... |
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Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2)
10.1021/acsmedchemlett.7b00427 2018-04-10 Tryptophan 2,3-dioxygenase 2 (TDO2) catalyzes the conversion of tryptophan to the immunosuppressive metabolite kynurenine. TDO2 overexpression has been observed in a number of cancers; therefore, TDO inhibition may be a useful therapeutic intervention for can... |
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Design, Synthesis, and X-ray of Selenides as New Class of Agents for Prevention of Diabetic Cerebrovascular Pathology
10.1021/acsmedchemlett.8b00076 2018-04-10 A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for their inhibition on six human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms such as the physiologically relevant hCA I, II, VA, VB, VII, and IX and the X-r... |
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Strategy for Extending Half-life in Drug Design and Its Significance
10.1021/acsmedchemlett.8b00018 2018-04-04 Preclinical optimization of compounds toward viable drug candidates requires an integrated understanding of properties that impact predictions of the clinically efficacious dose. The importance of optimizing half-life, unbound clearance, and potency and how t... |
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Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors
10.1021/acsmedchemlett.7b00487 2018-04-02 In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor 10 showed excelle... |
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Rhodanine as a Potent Scaffold for the Development of Broad-Spectrum Metallo-β-lactamase Inhibitors
10.1021/acsmedchemlett.7b00548 2018-03-26 A series of rhodanines was constructed, their Z-configuration was confirmed by small molecule X-ray crystal structures, and their activity against metallo-β-lactamases (MβLs) was measured. The obtained 26 molecules and a thioenolate specifically inhibited the... |
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Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8
10.1021/acsmedchemlett.8b00011 2018-03-21 Cortistatin A is a natural product isolated from the marine sponge Corticium simplex and was found to be a potent and selective inhibitor of CDK8. Many synthetic groups have reported total syntheses of Cortistatin A; however, these syntheses require between 1... |