Insulin sensitizers in 2023: lessons learned and new avenues for investigation.

Introduction: 'Insulin sensitizers' derived discoveries of the Takeda Company in 1970s. Pioglitazone remains the best in class with beneficial pleiotropic pharmacology, although use is limited by tolerability issues. Various attempts to expand out of this class assumed the primary molecular target was the transcription factor, PPARγ.

A DUAL MTOR/NAD+ ACTING GEROTHERAPY.

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging.

Synthesis and bioactivity of readily hydrolysable novel cationic lipids for potential lung delivery application of mRNAs.

Lipid nanoparticles (LNPs) mediated mRNA delivery has gained prominence due to the success of mRNA vaccines against Covid-19, without which it would not have been possible. However, there is little clinical validation of this technology for other mRNA-based therapeutic approaches. Systemic administration of LNPs predominantly targets the liver, but delivery to other organs remains a challenge.

Property-Driven Design and Development of Lipids for Efficient Delivery of siRNA.

Ionizable cationic lipids are critical components involved in nanoparticle formulations, which are utilized in delivery platforms for RNA therapeutics. While general criteria regarding lipophilicity and measured p in formulation are understood to have impacts on utility , greater granularity with respect to the impacts of the structure on calculated and measured physicochemical parameters and the subsequent performance of those ionizable cationic lipids in studies would be beneficial. Herein, we describe structural alterations made within a lipid class exemplified by , which allow us to tune calculated and measured physicochemical parameters for improved performance, resulting in substantial improvements versus the state of the art at the outset of these studies, resulting in good activity within a range of measured basicity (p = 6.

Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases.

Insulin-sensitizing thiazolidinediones (TZDs) correct a root cause of type 2 diabetes and potentially other diseases of metabolic dysfunction, including conditions ranging from oncologic, inflammatory, and neurodegenerative diseases. Importantly, compounds with this mode of action can modify disease progression, as opposed to simply mitigating symptoms. However, side effects have limited the use of marketed agents.

Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1).

Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine.

Design and synthesis of novel N-hydroxy-dihydronaphthyridinones as potent and orally bioavailable HIV-1 integrase inhibitors.

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.

Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK.

HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways.

The design and development of 2-aryl-2-hydroxy ethylamine substituted 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides as inhibitors of human cytomegalovirus polymerase.

Discovery efforts were focused on identifying a non-nucleoside antiviral for treating infections caused by human cytomegalovirus (HCMV) with equal or better potency and diminished toxicity compared to current therapeutics. This Letter describes the HCMV DNA polymerase inhibition and in vitro antiviral activity of various 2-aryl-2-hydroxy ethylamine substituted 1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides.

Azaindole hydroxamic acids are potent HIV-1 integrase inhibitors.

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships.

2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridines as broad-spectrum inhibitors of human herpesvirus polymerases.

A novel series of 2-aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides have been identified as potent antivirals against human herpesviruses. These compounds demonstrate broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases.

Furan-Terminated N-Acyliminium Ion Initiated Cyclizations in Alkaloid Synthesis.

A study of the utility of furan-terminated N-acyliminium ion initiated cyclizations for the synthesis of linearly fused alkaloid precursors (Figure 2) is presented. The outcome of the cyclization event depends on the position of furan tether attachment (2 vs 3), tether length, and furan 5-substituent (R = H, CH(3), Ar). 3-Substituted furans cyclized to form 6- and 7-membered ring containing furans 35-38, 50, and 51 in good to excellent yields.