Topic
Lead compound
About: Lead compound is a research topic. Over the lifetime, 838 publications have been published within this topic receiving 11565 citations.
Papers published on a yearly basis
1 / 2
Papers
TL;DR: The complex structure–activity relationships associated with biologically active molecules mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compound depending on its changed mode of action, physicochemical properties, target interaction, or metabolic susceptibility and transformation.
Abstract: The task of inventing and developing active ingredients with useful biological activities requires a search for novel chemical substructures. This process may trigger the discovery of whole classes of chemicals of potential commercial interest. Similar biological effects can often be achieved by completely different compounds. However, compounds within a given structural family may exhibit quite different biological activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compound, its interaction with the active site of the target protein, as well as its physicochemical, pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated organic compounds represent an important and growing family of commercial agrochemicals. A number of recently developed agrochemical candidates represent novel classes of chemical compounds with new modes of action; several of these compounds contain new fluorinated substituents. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compound depending on its changed mode of action, physicochemical properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a molecule at which fluorine substitution will result in optimal desired effects.
1,226 citations
TL;DR: A new X-ray crystallography–driven screening technique that combines the steps of lead identification, structural assessment, and optimization, which is rapid, efficient, and high-throughput, and it results in detailed crystallographic structure information.
Abstract: The need to decrease the time scale for clinical compound discovery has led to innovations at several stages in the process, including genomics/proteomics for target identification, ultrahigh-throughput screening for lead identification, and structure-based drug design and combinatorial chemistry for lead optimization. A critical juncture in the process is the identification of a proper lead compound, because a poor choice may generate costly difficulties at later stages. Lead compounds are commonly identified from high-throughput screens of large compound libraries, derived from known substrates/inhibitors, or identified in computational prescreeusing X-ray crystal structures. Structural information is often consulted to efficiently optimize leads, but under the current paradigm, such data require preidentification and confirmation of compound binding. Here, we describe a new X-ray crystallography-driven screening technique that combines the steps of lead identification, structural assessment, and optimization. The method is rapid, efficient, and high-throughput, and it results in detailed crystallographic structure information. The utility of the method is demonstrated in the discovery and optimization of a new orally available class of urokinase inhibitors for the treatment of cancer.
342 citations
TL;DR: The piperazinedione 12a, tadalafil, has been identified as a highly potent PDE5 inhibitor with high selectivity for PDE4 vs PDE1-4 and PDE6 and the cis-(6R,12aR) enantiomer displaying the highest PDE 5 inhibitory activity.
Abstract: Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
318 citations
TL;DR: 3s was obtained as lead compound with promising anticancer, anti-inflammatory and antioxidant activities and was confirmed to be nontoxic by in vitro cytotoxicity study.
310 citations
TL;DR: SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a possessed a weak competitive H1-antagonistic activity, so compound ADS-531 was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors.
Abstract: H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS-531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior.
187 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2026 | 1 |
| 2025 | 32 |
| 2024 | 49 |
| 2023 | 93 |
| 2022 | 195 |
| 2021 | 69 |