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Kappa opioid receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu opioid receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing –S– → –CH 2 – replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure–activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1. [Display omitted] • The kappa opioid receptor (KOR) is a target for the treatment of pain and itch. • Most KOR agonists cause dysphoria, a problematic side effect. • Biased KOR agonist selective for G-protein activation reduce dysphoria. • We report carbon-substituted triazoles as biased KOR agonists and examine their SAR. • A binding mode of this class to the KOR is proposed. [ABSTRACT FROM AUTHOR]

Impaired expression of GABA transporters (GATs) is closely related to the pathogenesis of among others Parkinson's disease and epilepsy. As such, lipophilic nipecotic acid analogs have been extensively studied as GAT1-addressing drugs and radioligands but suffer from limited brain uptake due to the zwitterionic properties of the nipecotic acid moiety. Bioisosteric replacement of the carboxylic acid group is a promising strategy to improve the brain uptake, though it requires knowledge on the binding of these isosteres to GAT1. To screen nipecotic acid isosteres for their affinity to GAT1 in a time- and cost-effective manner, this research aims to develop a molecular imprinted polymer (MIP) that mimics the natural binding site of GAT1 and can act as an alternative screening tool to the current radiometric and mass spectrometry cellular-based assays. To this end, a nipecotic acid MIP was created using the electropolymerization of ortho -phenylenediamine (oPD) by cyclic voltammetry (CV). The optimization of the generated receptor layer was achieved by varying the scan rate (50–250 mV/s) and number of CV cycles (5–12), yielding an optimized MIP with an average imprinting factor of 2.6, a linear range of 1–1000 n m , and a theoretical LOD of 0.05 n m , as analyzed by electrical impedance spectroscopy (EIS). Selectivity studies facilitated the investigation of major binding interactions between the MIP and the substrate, building an experimental model that compares characteristics of various analogs. Results from this model indicate that the substrate carboxylic acid group plays a more important role in binding than an amine group, after comparing the binding of cyclohexanecarboxylic acid (average IF of 1.7) and piperidine (average IF of 0.46). The research culminates in a discussion regarding the feasibility of the in vitro model, comparing the synthetic system against the biological performance of GAT1. Thus, evaluating if it is possible to generate a synthetic GAT1 mimic, and if so, provide directions for follow-up research. A nipecotic acid molecular imprinted polymer (MIP) was developed with a view to generating an artificial GAT1 mimic to allow in vitro screening of nipecotic acid bioisosteres. After selection, well-binding isosteres might be used to develop more viable GAT1-addressing drugs and radioligands. [Display omitted] • GAT1 mimic can allow time- and cost-effective screening of nipecotic acid isosteres. • A nipecotic acid molecular imprinted polymer was developed as artificial GAT1 mimic. • The developed synthetic system is compared against biological performance of GAT1. [ABSTRACT FROM AUTHOR]

Macrocyclization presents a valuable strategy for enhancing the pharmacokinetic and pharmacodynamic profiles of short bioactive peptides. The exploration of various macrocyclic characteristics, such as crosslinking tethers, ring size, and orientation, is generally conducted during the early stages of development. Herein, starting from a potent and selective C-X-C chemokine receptor 4 (CXCR4) cyclic heptapeptide antagonist mimicking the N-terminal region of CXCL12, we demonstrated that the disulfide bridge could be successfully replaced with a side-chain to side-chain lactam bond, which is commonly not enlisted among the conventional disulfide mimetics. An extensive investigation was carried out to explore the chemical space of the resulting peptides, including macrocyclization width, stereochemical configuration, and lactam orientation, all of which were correlated with biochemical activity. We identified a novel heptapeptide that fully replicates the pharmacological profile of the parent peptide on CXCR4, including its potency, selectivity, and antagonistic activity, while demonstrating enhanced stability in a reductive environment. At this stage, computational studies were instructed to shed light on how the lactam cyclization features influenced the overall structure of 21 and, in turn, its ability to interact with the receptor. We envisage that these findings can give new momentum to the use of lactam cyclization as a disulfide bond mimetic and contribute to the enhancement of the repertoire for peptide-based drug development, thereby paving the way for novel avenues in therapeutic innovation. [Display omitted] • A novel CXCR4 antagonist was developed by substituting a disulfide bond with side-chain to side-chain macrolactamization. • The new peptide exhibited low-nanomolar affinity and high selectivity for CXCR4 over the related receptor CXCR7. • The new peptide showed enhanced stability in a reductive environment compared to the parent disulfide-bridged peptide. • Molecular docking studies revealed how the orientation of the lactam bridge affects the activity of the developed peptide. [ABSTRACT FROM AUTHOR]

A structure-based drug design approach was focused on incorporating phenyl ring heterocyclic bioisosteres into coumarin derivative 1 , previously reported as potent dual AChE-MAO B inhibitor, with the aim of improving drug-like features. Structure-activity relationships highlighted that bioisosteric rings were tolerated by h MAO B enzymatic cleft more than h AChE. Interestingly, linker homologation at the basic nitrogen enabled selectivity to switch from h AChE to h BChE. In the present work, we identified thiophene-based isosteres 7 and 15 as dual AChE-MAO B (IC 50 = 261 and 15 nM, respectively) and BChE-MAO B (IC 50 = 375 and 20 nM, respectively) inhibitors, respectively. Both 7 and 15 were moderately water-soluble and membrane-permeant agents by passive diffusion (PAMPA-HDM). Moreover, they were able to counteract oxidative damage induced by both H 2 O 2 and 6-OHDA in SH-SY5Y cells and predicted to penetrate into CNS in a cell-based model mimicking blood-brain barrier. Molecular dynamics (MD) simulations shed light on key differences in AChE and BChE recognition processes promoted by the basic chain homologation from 7 to 15. [Display omitted] • Structure-based design of MTDLs was guided by phenyl ring bioisosteric mimicry. • 7 was the most potent hAChE-hMAO B inhibitor (IC 50 = 261 and 15 nM, respectively). • Linker homologation promoted ChEs selectivity switch, improving hBChE inhibition. • 15 was the most potent hBChE-hMAO B inhibitor (IC 50 = 375 and 20 nM, respectively). • Compounds 7 and 15 were drug-like cytoprotective agents against oxidative insults. [ABSTRACT FROM AUTHOR]

[Display omitted] Carboxylic acids are key pharmacophoric elements in many molecules. They can be seen as a problem by some, due to perceived permeability challenges, potential for high plasma protein binding and the risk of forming reactive metabolites due to acyl-glucuronidation. By others they are viewed more favorably as they can decrease lipophilicity by adding an ionizable center which can be beneficial for solubility, and can add enthalpic interactions with the target protein. However, there are many instances where the replacement of a carboxylic acid with a bioisosteric group is required. This has led to the development of a number of ionizable groups which sufficiently mimic the carboxylic acid functionality whilst improving, for example, the metabolic profile of the molecule in question. An alternative strategy involves replacement of the carboxylate by neutral functional groups. This review initially details carefully selected examples whereby tetrazoles, acyl sulfonamides or isoxazolols have been beneficially utilized as carboxylic acid bioisosteres altering physicohemical properties, interactions with the target and metabolism and/or pharmacokinetics, before delving further into the binding mode of carboxylic acid derivatives with their target proteins. This analysis highlights new ways to consider the replacement of carboxylic acids by neutral bioisosteric groups which either rely on hydrogen bonds or cation-π interactions. It should serve as a useful guide for scientists working in drug discovery. [ABSTRACT FROM AUTHOR]

[Display omitted] Herein, we present a synthetic compound library comprising of 13 structurally diverse heterocyclic monosquarate-amide derivatives. The compounds featured in this library were designed as potential bioisosteric replacements carboxylic acid moiety's. A good selection of the compounds presented exhibit unique molecular architecture and have shown promising results following in silico evaluation of 'druglike properties' using Swiss ADME. The research presented in this work focuses on the preparation of derivatives of 3,4-dihydroxycyclobut-3-ene-1,2-dione, a known carboxylic acid bioisostere. [ABSTRACT FROM AUTHOR]

Abstract Nuclear receptor RXRα plays an important role in many biological and pathological processes. The nongenomic action of RXRα is implicated in many cancers. K-8008, a non-canonical RXRα ligand derived from sulindac, inhibits the TNFα-activated PI3K/AKT pathway by mediating the interaction between a truncated form of RXRα (tRXRα) and the p85α regulatory subunit of PI3K and exerts potent anticancer activity in animal model. Herein we report our studies of a novel series of K-8008 analogs as potential anticancer agents targeting RXRα. Two compounds 8b and 18a were identified to have slightly stronger binding to RXRα and improved apoptotic activities in breast cancer cells. Graphical abstract Image 1 Highlights • Four series of sulindac analogs (26 compounds) were designed and synthesized. • 8b and 18a have improved binding affinity and apoptotic activity against breast cancer cells. • 8b and 18a can induce the PARP cleavage in a RXRα-dependent manner. [ABSTRACT FROM AUTHOR]

Abstract Two series of andrographolide derivatives with nitrogen-containing heterocycles, phenols and aromatic acids as bioisostere moiety of lactone ring were synthesized. 8 from 18 tested compounds showed stronger inhibitory effect on LPS-induced NO production in RAW264.7 macrophage than hydrocortisone. Among them, compound 8m exhibited the most potent inhibition with IC 50 of 3.38 ± 1.03 μM. The structure-activity relationships (SARs) suggested that the replacement of lactone ring with small-molecule phenols could improve the anti-inflammatory efficacy. Furthermore, compound 8m significantly reduced the levels of pro-inflammatory cytokine IL-1β and IL-6 with no influence on cell survival, decreased the expression of iNOS and COX-2, and down-regulated the level and phosphorylation of IκBα, as well as the expression of NF-κB. Also it blocked the nuclear translocation of NF-κB in LPS-induced macrophage. Therefore, the anti-inflammation mechanism of compound 8m was related to the inhibition of COX-2, iNOS and NF-κB signal pathway. Graphical abstract Image 1 Highlights • The derivatives of andrographolide with different skeletons as bioisostere of lactone ring were synthesized. • Small-molecule phenols as bioisostere of lactone ring could improve the anti-inflammation efficacy of andrographolide. • Compound 8m showed the most potent inhibition on LPS-induced NO production in RAW264.7 macrophage. • Compound 8m suppressed LPS-induced NO, IL-1β and IL-6 production. • The anti-inflammatory action mechanism of 8m was related to the inhibition of COX-2, iNOS and NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

• A series of aminophenol derivatives were synthesized and structurally characterized to evaluate their PD-1/PD-L1 inhibitory potency. • Compound 11e and 20 could induce hPD-L1 to go non-covalent polymerization. • One of the obtained compounds (11e) showed a much higher rate in the inhibition of PD-1/PD-L1 interaction compared to resorcinol-containing compound 20. • One of the obtained compounds (11e) was capable of increasing the cytotoxic potency of CD8+ T cells with regard to killing human NSCLC cells compared to 20 and T cell alone. Discovery of novel small molecules blocking PD-1/PD-L1 interaction is a promising approach mobilizing immune system to fight against cancers. Herein we report the synthesis and identification of a series of aminophenol derivatives as a novel class of PD-1/PD-L1 inhibitors for cancer immunotherapy. Structure based design together with preliminary evaluation of each region of the molecular architecture resulted in identification of (R)-3-(5-chloro-2-((4-cyanobenzyl)oxy)-4-(((2-methyl-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)amino)benzyl)-2-oxooxazolidine-4-carboxylic acid (11e) with an IC 50 value of 21.3 nM. Compound 11e was demonstrated to be a highly potent hPD-L1 inhibitor and showed enhanced inhibitory potency compared to resorcinol derivative (compound 20). Compound 11e was capable of increasing the cytotoxic potency of CD8+ T cells with regard to killing human NSCLC cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A new series of SGLT1 and SGLT2 dual inhibitors were disclosed. • Two methods were developed to efficiently synthesize C 5 -fluoro-lactones 3 and 4. • Lead compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition. • Lead compound 2b showed robust in vivo efficacy in rodent models of diabetes. Abstract A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C 5 -fluoro-lactones 3 and 4 , which are key intermediates to the C 5 -fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC 50 = 43 nM for SGLT1 and IC 50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg. [ABSTRACT FROM AUTHOR]

Highlights • An injectable new prodrug was tested against immature and adult flukes. • The experimental compound exerts high efficacy against adults. • The new injectable fasciolicide used half the dose of the oral parent compound. • The solubilized alpha prodrug might reduce environmental contamination. Abstract The effective dose of an injectable prodrug, named compound alpha prodrug, against immature and adult Fasciola hepatica in experimentally infected sheep was determined. In a first experiment, 30 sheep were infected with Fasciola hepatica on day 0 and 50. After microscopic detection of faecal eggs on day 80, groups (n = 6) 1 to 3 were treated with 6, 8 and 10 mg/kg of the experimental water-soluble prodrug compound alpha intramuscularly, respectively. Group 4 was treated with closantel and group 5 remained untreated. Copromicroscopical examinations were made on day 0, 80 and 108. On day 110, trematodes were collected from the bile ducts. Fasciolicide efficacy was assessed as a percentage of fluke-egg and adult-fluke reduction. Fluke length was also recorded. In a second experiment aimed to assess the fasciolicide activity of compound alpha prodrug against four-week-old flukes, 12 sheep were infected on day 0 and allocated into two groups (n = 6). On day 50 post infection, group A was treated with the experimental water-soluble prodrug compound alpha at 6 mg/kg/IM and B remained untreated. Fasciolicide activity was assessed on day 80 after collection, microscopic observation and measurement of flukes present in the parenchyma for immature stages and on day 108 for adults. Egg output decreased 91.2, 96.0, 98.8 and 94.9% for groups 1, 2, 3 and 4, respectively. Compound alpha prodrug cleared 97.6%, 98.51% and 100% of adult stages in a dose-dependent manner. Closantel killed 81.95% flukes. Regarding the second experiment, 81.2% efficacy was achieved. Immature flukes were significantly smaller in the treated group. It is concluded that the intramuscular application of compound alpha prodrug exerted fasciolicide efficacy against adults of Fasciola hepatica. [ABSTRACT FROM AUTHOR]

Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na V 1.7 and demonstrate high levels of selectivity over other Na V isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective Na V 1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over Na V 1.5 and favorable pharmacokinetics in rodents. [ABSTRACT FROM AUTHOR]

Following a hybridization strategy, a series of 5-substituted-1 H -indazoles were designed and evaluated in vitro as inhibitors of human monoamine oxidase (h MAO) A and B. Among structural modifications, the bioisostere-based introduction of 1,2,4-oxadiazole ring returned the most potent and selective human MAO B inhibitor (compound 20 , IC 50 = 52 nM, SI > 192). The most promising inhibitors were studied in cell-based neuroprotection models of SH-SY5Y and astrocytes line against H 2 O 2. Moreover, preliminary drug-like features (aqueous solubility at pH 7.4; hydrolytic stability at acidic and neutral pH) were assessed for selected 1,2,4-oxadiazoles and compared to amide analogues through RP-HPLC methods. Molecular docking simulations highlighted the crucial role of molecular flexibility in providing a better shape complementarity for compound 20 within MAO B enzymatic cleft than rigid analogue 18. Enzymatic kinetics analysis along with thermal stability curves (T m shift = +2.9 °C) provided clues of a tight-binding mechanism for h MAO B inhibition by 20. [Display omitted] • Twentyfive 1 H -indazoles were designed and tested as h MAO inhibitors. • Bioisosteric amide replacement via 1,2,4-oxadiazoles was investigated. • Compound 20 was the most potent and selective MAO B inhibitor (IC 50 = 52 nM, SI > 192). • 20 protected both SH-SY5Y and astrocytes from H 2 O 2 insult. • 20 displayed tight-binder's features toward h MAO B (T m shift = +2.9 °C). [ABSTRACT FROM AUTHOR]

[Display omitted] • Bioisosterical transformation was attempted during fungicide discovery research. • [1,2,4]triazolo[1,5- a ]pyrimidine was transformed into pyridazine. • Structural simplification led us to a cost-effective compound, pyridachlometyl. • Pyridachlometyl is expected to be commercially available in 2024. Pyridachlometyl is a unique pyridazine fungicide with a novel mode of action. Herein, we describe the pathway for the invention of pyridachlometyl. First, we identified a diphenyl-imidazo[1,2- a ]pyrimidine as our proprietary lead with potent fungicidal activity. Then, aiming to simplify the chemical structure, we applied judicious estimations to explore monocyclic heterocycles as pharmacophores. This enabled the identification of a novel class of tetrasubstituted pyridazine compounds with potent fungicidal activity, likely retaining the same mode of action as the aforementioned compounds. The findings indicated bioisosteric similarity between diphenyl-imidazo[1,2- a ]pyrimidine and pyridazine. Further structure–activity and mammalian safety investigations of pyridazine compounds resulted in the discovery of pyridachlometyl as a candidate for commercial development. [ABSTRACT FROM AUTHOR]

The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, however inappropriate activity has also been implicated in certain auto-immune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro . Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection. [ABSTRACT FROM AUTHOR]

As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Ca v 3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca v 3.2 currents (>90% inhibition) at 10 μM concentration and exhibited cytotoxic effect (IC 50 = 5.9 μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Ca v 3.2 channels. [ABSTRACT FROM AUTHOR]

This letter presents synthesis and structure-activity relationship study of sulfonamide derivatives as inhibitors of Human Uric Acid Transporter 1 (hURAT1). Among all tested sulfonamide derivatives, compounds 9b , 16i and 19b exhibited excellent inhibition activity with IC 50 value of 10, 2, and 83 nM, respectively. In addition, compounds 9b and 19b demonstrated moderate PK profile in rats. [ABSTRACT FROM AUTHOR]

The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo . The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility. [ABSTRACT FROM AUTHOR]

Squaric acid and its derivatives are versatile synthons and have demonstrated applications in medicinal chemistry, notably as non-classical bioisosteric replacements for functional groups such as carboxylic acids, alpha-amino acids, urea, guanidine, peptide bonds and phosphate/pyrophosphate linkages. Surprisingly, no reports have appeared concerning its possible application as a nucleobase substitute in nucleosides. A preliminary investigation of such an application is reported herein. 3-Amino-4-((1 R ,4 S )-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione, 3-((1 R ,4 S )-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-4-methoxycyclobut-3-ene-1,2-dione, and 3-hydroxy-4-((1 R ,4 S )-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione sodium salt were synthesized. Computational analyses of their structures and preliminary antitumor and antiviral screening results are reported. [ABSTRACT FROM AUTHOR]

The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid ( 1 ) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N -acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis . Subsequent structure-activity relationship (SAR) studies identified several compounds with mixed antibacterial and antitubercular profiles. Compound 22 (IC 50 0.72, 0.51, 0.88, 0.49 μg/mL for Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus, Bacillus subtilis , respectively) exhibited similar antibacterial profile as 1 . The N -acetyl derivative 18 was similar to 1 in antitubercular profile. Thus, the present study successfully demonstrated the use of azaspiro substructure in the medicinal chemistry of antibacterial and antitubercular agents. [ABSTRACT FROM AUTHOR]

A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position ( 5 , 6 , 12 ) or by the application of alternative nitrogenous bases ( 18 ). Based on these results, CN-SAH ( 19 ) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms. [ABSTRACT FROM AUTHOR]

The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N -methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the ‘best’ one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound. [ABSTRACT FROM AUTHOR]

A series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2) H -pyrazolo[4,3- d ]pyrimidine derivatives was synthesized and evaluated for their cyclin-dependent kinase (CDK) inhibition activity. The most potent compounds contained various hydroxyalkylamines at the 5 position and possessed low nanomolar IC 50 values for CDK2 and CDK5. Preliminary profiling of one of the most active compounds on a panel of 50 protein kinases revealed its high selectivity for CDKs. The compounds arrested cells in S and G2/M phases, and induced apoptosis in various cancer cell lines. Significant dephosphorylation of the C-terminus of RNA polymerase II and focal adhesion kinase (FAK), well-established substrates of CDKs, has been found in treated cells. Cleavage of PARP-1, down-regulation of Mcl-1 and activation of caspases correlated well with CDK inhibition and confirmed apoptosis as the primary type of cell death induced in cancer cells treated with the compounds in vitro . A comparison of known purine-based CDK inhibitor CR8 with its pyrazolo[4,3- d ]pyrimidine bioisosteres confirmed that the novel compounds are more potent in cellular assays than purines. Therefore, pyrazolo[4,3- d ]pyrimidine may emerge as a novel scaffold in medicinal chemistry and as a source of potent CDK inhibitors. [ABSTRACT FROM AUTHOR]

Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b , 1c , 1e , 3c , and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC 50 = 0.35 μM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical modifications. [ABSTRACT FROM AUTHOR]

Evolution from a furan-containing high-throughput screen (HTS) hit ( 1 ) resulted in isobenzofuran-1(3 H )-one ( 2 ) as a potent inhibitor of the function of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 NK cells. In the current study, structure–activity relationship (SAR) development towards a novel series of diarylthiophene analogues has continued through the use of substituted-benzene and -pyridyl moieties as bioisosteres for 2-thioxoimidazolidin-4-one ( A ) on a thiophene ( B ) -isobenzofuranone ( C ) scaffold. The resulting compounds were tested for their ability to inhibit perforin lytic activity in vitro. Carboxamide ( 23 ) shows a 4-fold increase over ( 2 ) in lytic activity against isolated perforin and provides good rationale for continued development within this class. [ABSTRACT FROM AUTHOR]

The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human β 3 -adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human β 3 -adrenergic potency and good selectivity over the β 1 and β 2 receptors. In addition to human β 1 , β 2 , β 3 and hERG data, PK of selected compounds will be described. [ABSTRACT FROM AUTHOR]

Inhibition of translation initiation has emerging implications for the development of mechanism-based anticancer therapeutics. Phosphorylation of eIF2α is recognized as a key target that regulates the translation initiation cascade. Based on the bioisosteric replacement of urea-derived eIF2α phosphorylation activator 1 , a novel series of N -aryl- N′ -[4-(aryloxy)cyclohexyl]squaramide derivatives was designed and synthesized; their effects on the activation of eIF2α phosphorylation was assessed systematically. A brief structure–activity relationship analysis was established by stepwise structural optimization of the squaramide series. Subsequently, the antiproliferative activities of the selected analogues were determined in human leukemia K562 cells. We then identified 10 potent eIF2α phosphorylation activators with considerable anticancer activity. The most promising analogues 19 and 40 possessed higher cancer cell selectivity (SI = 6.16 and 4.83, respectively) than parent 1 (SI = 2.20). Finally, protein expression analysis revealed that compounds 19 and 40 induced eIF2α phosphorylation and its downstream effectors ATF4 and CHOP. [Display omitted] • A new series of squaramides was designed and synthesized by a bioisosteric approach. • Ten analogues induced p-eIF2α and antiproliferation in K562 cells with high IC 50 value. • 19 and 40 exhibited remarkably high selectivity index (6.16 and 4.83, respectively). • 19 and 40 increased the expression level of eIF2α downstream proteins, ATF and CHOP. [ABSTRACT FROM AUTHOR]

The introduction of silicon in biologically-relevant molecules represents an interesting medicinal chemistry tactic. Its use is mainly confined to the fine-tuning of specific molecular properties and organosilicon compounds are underrepresented in typical screening libraries. As part of the European Lead Factory efforts to generate novel, drug discovery-relevant chemical matter, the design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries is described. [ABSTRACT FROM AUTHOR]

Arabidopsis thaliana 7-Keto-8-AminoPelargonic Acid Synthase ( At KAPAS) is a crucial herbicide target, and At KAPAS inhibitors are widely available in the agrochemical market. The herbicide plumbagin is known as a potent inhibitor for At KAPAS but it is extremely toxic. In this study, we identified the metabolic site of plumbagin and also performed a similarity-based library analysis using 2D fingerprints and a docking study. Four compounds as virtual hits were derived from plumbagin. Treatment of Digitaria ciliaris with compound 2 , one of four hit compounds, stunted the growth of leaves and the leaf tissue was desiccated or burned within three days. Thus, we expect that compound 2 will be developed as a new herbicide and additionally our strategy will provide helpful information for optimizing lead compounds. [ABSTRACT FROM AUTHOR]

With the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach with implications for salvage and preexposure prophylactic regimens, as well as topical microbicides. Using the combination of a field-derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors. [ABSTRACT FROM AUTHOR]

2-Aminopyrimidin-4(1 H )-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1 H )-ones led to the discovery of the novel and potent CXCR2 antagonist 3e . 2-Aminopyrimidin-4(1 H )-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas. [ABSTRACT FROM AUTHOR]

[Display omitted] Dipeptidyl peptidase III (DPP3) is a ubiquitously expressed zinc-dependent peptide cutting enzyme and selectively hydrolyses amide bonds to cleave N -terminal dipeptide fragments off of physiologically important oligopeptides. DPP3 has been found in a multitude of different types of cells and appears to be involved in various physiological processes (e.g. nociception, blood pressure control, protein turnover). Using the slowly converted peptide substrate tynorphin (VVYPW) as starting point, we have replaced the scissile bond with a fluoroethylene bioisostere to design ground state inhibitors, which led to the so far most effective peptide-based inhibitor of DPP3. [ABSTRACT FROM AUTHOR]

One pot synthesis and characterization of new 5-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridines ( 3a–k ) using amides ( 2a–k ) were reported. The prepared 5-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine ( 3a ) is a bioisostere of 4′-(6,7-dihydro-4H-thieno [3,2-c]pyridin-5-ylmethyl)-biphenyl-2-carboxylic acid ( 1 ), having good in vivo antithrombotic activity compared with Clopidogrel. The new tetrazole derivatives ( 3a–k ) were screened for their in vitro activity as platelet aggregation inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: The fragment of 2-substituted-3-sulfonylaminobenzamide has been proposed to replace the fragment of 2-substituted-3-sulfonylaminopyridine in PI3K and mTOR dual inhibitors to design novel anticancer agents based on bioisostere. The combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2-amino[1,2,4]triazolo[1,5-a]pyridine produced the novel structures of anticancer agents. As a result, nineteen target compounds were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines including HCT-116, A549, MCF-7 and U-87 MG. The SAR of target compounds was preliminarily discussed. Compound 1g with potent antiproliferative activity was examined for its effect on the AKT and p-AKT473. The anticancer effect of 1g was evaluated in established nude mice HCT-116 xenograft model. The results suggested that compound 1g can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. These findings strongly support our assumption that the fragment of benzamide can replace the pyridine ring in some PI3K and mTOR dual inhibitor to design novel anticancer agents. [Copyright &y& Elsevier]

Abstract: Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2–10 fold selectivity over a panel of PTP’s. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies. [Copyright &y& Elsevier]

Abstract: A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition. [Copyright &y& Elsevier]

Abstract: 2-Substituted-3-sulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides have been proposed as novel structures of PI3K inhibitors and anticancer agents based on bioisostere. In the present study, 2-substituted-3-sulfonamino-5-(4-morpholinoquinazolin-6-yl)benzamides and 2-methoxy-3-sulfonamino-5-(4-morpholinoquinolin-6-yl)benzamides were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines, including A549, HCT-116, U-87 MG and KB. The SAR of the title compounds was preliminarily discussed. Compound 1a with potent antiproliferative activity was tested for its inhibitory activity against PI3K and mTOR and its effect on the AKT and p-AKT473. The anticancer effect of 1a was evaluated in established nude mice U-87 MG xenograft model. The results suggest that compound 1a can significantly inhibit PI3K/AKT/mTOR pathway and tumor growth. These findings strongly support the assumption that title compounds are potent PI3K inhibitors and anticancer agents. [Copyright &y& Elsevier]

Abstract: Regiochemical control in the functionalization of ambident nucleophiles is of particular interest in organic chemistry. Herein, we demonstrate that O-alkylation of ambident 3-hydroxyisoxazoles, which are heterocyclic bioisosteres of carboxylic acids, predominates under Mitsunobu conditions. In several cases, excellent O-regioselectivity (⩾95%) was observed. It is noteworthy that reactions were complete within 15min at room temperature. Furthermore, the conditions are compatible with a range of alcohols that cover all of the typical protecting groups for the 3-hydroxyisoxazole motif, providing milder, simpler and less hazardous protocols to those commonly followed in the literature. [Copyright &y& Elsevier]

Abstract: Compounds 1–10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated. Compounds 5 (α-series) and 10 (β-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 μM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11β-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π–π interactions between the naphthyl group and Tyr177. [Copyright &y& Elsevier]

Abstract: 5-Oxaprotoberberinones and 5-oxaprotoberberinium were synthesized as bioisosteres of protoberberines. 5-Oxaprotoberberinones were prepared by linking phenol with the isoquinolone ring of 3-phenolisoquinolones by methyleneoxy bridge, while the quaternary 5-oxaprotoberberinium salt was synthesized by reduction and oxidation of the lactam moiety of 5-oxaprotoberberinone. [Copyright &y& Elsevier]

Abstract: Activators of the pyruvate kinase M2 (PKM2) are currently attracting significant interest as potential anticancer therapies. They may achieve a novel antiproliferation response in cancer cells through modulation of the classic ‘Warburg effect’ characteristic of aberrant metabolism. In this Letter, we describe the optimization of a weakly active screening hit to a structurally novel series of small molecule 3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as potent PKM2 activators. [Copyright &y& Elsevier]

Abstract: We have previously reported a series of 2,4,6-trisubstituted pyrimidines as potent A2A receptor antagonists. The leading compounds often feature a potentially labile acetamide functional group which tends to hydrolyze under acidic conditions. Here we report the replacement of the acetamide functional group with bioisosteres. This effort led us to a new series of adenosine A2A receptor antagonists with improved potency and chemical stability. [Copyright &y& Elsevier]

[Display omitted] The pharmacological actions exerted by benzodiazepines are dependent on the discrete α protein subunits of the γ-aminobutyric acid type A receptor (GABA A R). Recent developments via a cryo-EM structure of the α1β3γ2L GABA A R ion channel provide crucial insights into ligand efficacy and binding affinity at this subtype. We investigated the molecular interactions of diazepam and alprazolam bound GABA A R structures (6HUP and 6HUO) to determine key binding interaction domains. A halogen bond between the chlorine atoms of diazepam and alprazolam with the group on the backbone of the α1 histidine amino acid 102 is important to the positive allosteric modulatory actions of diazepam and alprazolam in the α1β3γ2L GABA A R ion channel. In order to gain insight into α subtype selectivity we designed and synthesized close structural analogs of diazepam and alprazolam. These compounds were then docked into the recently publish cryo-EM structures of GABA A Rs (6HUP and 6HUO). This modeling along with radio-ligand binding data resulted in the conclusion that the non-classical bioisosteric replacement of the chlorine atom at C7 with an ethinyl group (compound 5) resulted in an 11-fold gain in α5 binding selectivity over the α1 subtype. Moreover, the potency of compound 5 resulted in a ligand with less sedation than diazepam, while still maintaining the same anxiolytic potency. These modeling data extend our understanding of the structural requirements for α-subtype-selective compounds that can be utilized to achieve improved medical treatments. It is clear that the ethinyl group in place of a halogen atom decreases the affinity and efficacy of benzodiazepines and imidazodiazepines at α1 subtypes, which results in less sedation and ataxia. [ABSTRACT FROM AUTHOR]

The synthesis of five series of 4′-truncated nucleoside phosphonic acid analogues is discussed in this review: (1) 4′-truncated furanose nucleoside phosphonic acid analogues; (2) 4′-truncated pyrrolidine nucleoside phosphonic acid analogues; (3) 4′-truncated carbocyclic nucleoside phosphonic acid analogues; (4) 4′-truncated isoxazole nucleoside phosphonic acid analogues; (5) 4′-truncated miscellaneous nucleoside phosphonic acid analogues. Five different ways are used to make the phosphonate moiety: (i) Michaelis-Arbuzov reaction of RX (X = Br, I, OTf) with trialkyl phosphate; (ii) Lewis acid catalyzed Michaelis-Arbuzov reaction of glycoside with trialkyl phosphite; (iii) nucleophilic addition of a dialkyl phosphite to a carbonyl group; (iv) direct coupling reaction with amino alkyl phosphonate; (v) de novo synthesis of phosphonated-isoxazole and 1,3-dioxolane heterocycles from phosphonated starting materials. Their biological activity results are briefly discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Chiral substituted phenylethyl-1H-tetrazoles were built-up from the corresponding carboxylic acid derivatives by a useful three-step synthesis. The procedure, that preserves the chiral center from racemization, was successfully applied to a selection of several hit compounds by conversion of the carboxylic acid moiety to the nitrile derivatives and subsequent reaction with trimethylstannyl azide, under microwave conditions. A useful application to the corresponding tetrazole analogue has been found also in the conversion of the aminoacidic moiety like (R)-N-Cbz-phenylglycine showing a wide potential synthetic application. [Copyright &y& Elsevier]

Abstract: Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a–2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-β-diketones (5a–5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H2S gas in the presence of triethylamine. All the synthesized compounds (2a–2i and 3a–3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3–4h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data. [Copyright &y& Elsevier]

Abstract: Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation. [Copyright &y& Elsevier]

Abstract: 2-Arylamino-4-aryl-pyrimidines were found to be potent inhibitors of PAK1 kinase. The synthesis and SAR are described. The incorporation of a bromide at the 5-position of the pyrimidine core and in combination with a 1,2-dimethylpiperazine pendant domain yielded a lead compound with potent PAK1 inhibition and anti-proliferative activity in various colon cancer cell lines. [Copyright &y& Elsevier]

Abstract: Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifications at the “homocysteine” part of the previously reported potent inhibitor (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid (1). In the new compounds, which are S-alkylated homocysteine derivatives, we replaced the carboxylic group in the “homocysteine” part of inhibitor 1 with different isosteric moieties (tetrazole and oxadiazolone); we suppressed the carboxylic negative charge by amidations; we enhanced acidity by replacing the carboxylate with phosphonic or phosphinic acids; and we introduced pyrrolidine steric constraints. Some of these compounds display high affinity toward human BHMT and may be useful for further pharmacological studies of this enzyme. Although none of the new compounds were more potent inhibitors than the reference inhibitor 1, this study helped to completely define the structural requirements of the active site of BHMT and revealed the remarkable selectivity of the enzyme for homocysteine. [Copyright &y& Elsevier]

Abstract: The potential roles of 11β-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11β-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl–oxadiazole derivatives as human 11β-HSD1 inhibitors, we explored the structure–activity relationship of several parts of the lead compound. Based on their potency toward human 11β-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11β-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model. [Copyright &y& Elsevier]