Papers by nicholas meanwell
ACS Medicinal Chemistry Letters, Aug 9, 2018
The awareness of frequent hitters in high-throughput screening campaigns, termed pan-assay interf... more The awareness of frequent hitters in high-throughput screening campaigns, termed pan-assay interference compounds (PAINS), was heightened considerably by the classification of a series of structural alerts that defined problematic compounds presenting as cryptically active leads that typically produced flat structureactivity relationships and could not be further optimized. In the present issue, Vidler et al. (DOI: 10.1021/acsmedchemlett.8b00097) extend this study by analyzing an extensive and high quality screening data set harvested from the Lilly corporate database that examines the behavior of a large number of the PAINS structural alerts in over 3000 unique assays using multiple analytical formats. Only two of the PAINS substructure alerts, 1,4-diaminobenzene and rhodanine, showed significant pan-assay promiscuity, but these appeared to be enriched in AlphaScreen assays. A much larger fraction of the PAINS structural alerts were enriched for compound instability or the presence of a high Hill slope value indicative of greater than 1:1 compound/protein binding stoichiometry. A number of the alerts also enriched for cytotoxicity, indicating that cell-based assays may be inadequate for confirming the activity of molecules that incorporate a PAINS alert. This analysis provides additional insight into the interpretation of PAINS alerts and may help to reduce the propensity to pursue false positive leads.
Elsevier eBooks, 2008
This chapter updates and expands upon the material presented in CHEC(1984) and CHEC-II(1996), dra... more This chapter updates and expands upon the material presented in CHEC(1984) and CHEC-II(1996), drawing upon the literature published between the beginning of 1995 and the end of 2006. Theoretical methods and the application of spectroscopy in the determination of structure and conformation are discussed followed by a description of thermodynamic aspects of both 1,4-diazepines and the benzo-fused homologues that examine the deeper, emerging understanding of conformational preferences for this class of heterocycles. Reactivity associated with fully conjugated (unsaturated) and nonconjugated (saturated) ring systems are summarized followed by the reactivity associated with substituents attached to ring carbon and nitrogen atoms. New synthetic approaches to the 1,4-diazepine ring system continue to be developed that provide access to a broader range of functionalized derivatives and allow further elaboration. Synthetic approaches are categorized based on bond-disconnection topology and approaches previously discussed are updated where new methodology or reagents have been developed. New bond disconnections are summarized in sections that are expanded over the previous editions. 1,4-Diazepines and fused ring analogues are important structural scaffolds in medicinal chemistry, recognized as privileged structures, that display a broad range of biological activities, and representative compounds are presented.
Bioorganic & Medicinal Chemistry
Antimicrobial Agents and Chemotherapy, 2021
HIV-1 maturation inhibitors (MIs) offer a novel mechanism of action and potential for use in HIV-... more HIV-1 maturation inhibitors (MIs) offer a novel mechanism of action and potential for use in HIV-1 treatment. Prior MIs displayed clinical efficacy but were associated with the emergence of resistance and some gastrointestinal tolerability events.
Bioorganic & Medicinal Chemistry Letters, 2021
GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown... more GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp3-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.
Journal of Medicinal Chemistry, 2020
Bioorganic & Medicinal Chemistry Letters, 2020
Journal of medicinal chemistry, Jan 22, 2017
Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs t... more Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. The indole-3-glyoxamide 6 was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir (31), which exhibited an improved antiviral and pharmacokinetic profile compared to 6 and was explored in phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir (35), a prodrug designed to address dissolution- and solubility-limited absorption issues. In this drug annotation, we summarize the structure-activity and structure-liability studies leading to the discovery of 31 and the clinical studies conducted with 35 that entailed the development of an extended relea...
ACS Medicinal Chemistry Letters
Journal of Agricultural and Food Chemistry
Journal of Medicinal Chemistry
Bioorganic & Medicinal Chemistry Letters
Advances in Experimental Medicine and Biology
Gp120 is a critical viral proteins required for HIV-1 entry and infection. It facilitates HIV-1 b... more Gp120 is a critical viral proteins required for HIV-1 entry and infection. It facilitates HIV-1 binding to target cells, human-to-human transmission, relocation of virus from mucosa to lymph nodes, cell-cell infection and syncytium formation, and the bystander effect that kills uninfected CD4+ T-cells and other human cells. Molecules that bind to gp120 can inhibit its function by stabilizing conformations of the protein, leading to the inability to infect cells, and resulting in non-permissive. Small molecule-mediated stabilization of certain conformations of gp120 may also enhance recognition of HIV-1 infected cells by neutralizing antibodies and make the virus more susceptible to effector functions such as ADCC, which could potentially be part of future cure regimens. Additionally, HIV attachment inhibitors can complex with free gp120 and potentially repress both cytopathic effects from membrane-bound or soluble gp120. Fostemsavir (RukobiaTM), a phosphate prodrug of an HIV-1 attachment inhibitor that was recently approved for use in highly treatment experienced (HTE) patients with multidrug resistant HIV-1 is a first-in-class drug with a favorable safety profile that provides an additional treatment option for treatment in this population of patients with a high medical need.
Journal of Medicinal Chemistry, 2022
Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their n... more Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29.
Tetrahedron, 2021
Abstract The dearomatizing photocycloaddition reaction is a powerful and effective strategy for s... more Abstract The dearomatizing photocycloaddition reaction is a powerful and effective strategy for synthesizing complex, three-dimensional, polycyclic scaffolds from simple aromatic precursors. Generally, the dearomatizing photocycloaddition reaction is promoted by visible light and occurs via an energy transfer (EnT) process. This mini-review provides an overview of recent advances in this area (2018–2020), encompassing both intramolecular and intermolecular transformations. While the majority of the studies are centered on intramolecular processes due to their predictable regio- and stereo-selectivity, intermolecular transformations that show an exceptionally broad substrate scope are beginning to emerge.
ACS Medicinal Chemistry Letters, 2018
Photodynamic antimicrobial chemotherapy, in which light is used to activate a photosensitizer (PS... more Photodynamic antimicrobial chemotherapy, in which light is used to activate a photosensitizer (PS) to generate cytotoxic oxidants from 3 O 2 , suffers from the drawback of designing specificity for bacterial membranes while sparing host cells. In the present issue, Sol et al.
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Papers by nicholas meanwell