Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects

We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED₅₀ of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.     

Synthesis,biological evaluation and 3D-QSAR studies of 1,2,4-triazole-5-substituted carboxylic acid bioisosteres as uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia associated with gout

As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 inhibitor activity (IC₅₀). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 inhibitor 1g, which was 225-fold more potent than the parent lesinurad in vitro (IC₅₀?=?0.032?μM for 1g against human URAT1 vs 7.20?μM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher’s randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization.     

Design and synthesis of a novel 1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative as an orally available ACC1 inhibitor

We initiated our structure-activity relationship (SAR) studies for novel ACC1 inhibitors from 1a as a lead compound. Our initial SAR studies of 1H-Pyrrolo[3,2-b]pyridine-3-carboxamide scaffold revealed the participation of HBD and HBA for ACC1 inhibitory potency and identified 1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1c as a potent ACC1 inhibitor. Although compound 1c had physicochemical and pharmacokinetic (PK) issues, we investigated the 1H-pyrrolo[3,2-b]pyridine core scaffold to address these issues. Accordingly, this led us to discover a novel 1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1k as a promising ACC1 inhibitor, which showed potent ACC1 inhibition as well as sufficient cellular potency. Since compound 1k displayed favorable bioavailability in mouse cassette dosing PK study, we conducted in vivo Pharmacodynamics (PD) studies of this compound. Oral administration of 1k significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at a dose of 100 mg/kg. Accordingly, our novel series of potent ACC1 inhibitors represent useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.     

Triazine and pyrimidine based ROCK inhibitors with efficacy in spontaneous hypertensive rat model

The profile of a series of triazine and pyrimidine based ROCK inhibitors is described. An initial binding mode was established based on a homology model and the proposed interactions are consistent with the observed SAR. Compounds from the series are potent in a cell migration assay and possess a favorable kinase selectivity. In vivo activity was demonstrated for compound 1A in a spontaneous hypertensive rat model.     

Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors

A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure–activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.     

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.     

Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 2: Structure–activity relationships (SAR) of the C3-phenyl moiety

Detailed structure–activity relationships of the C3-phenyl moiety that allow for the optimization of antiviral potency of a series of 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione inhibitors of HIV capsid (CA) assembly are described. Combination of favorable substitutions gave additive SAR and allowed for the identification of the most potent compound in the series, analog 27. Productive SAR also transferred to the benzotriazepine and spirobenzodiazepine scaffolds, providing a solution to the labile stereocenter at the C3 position. The molecular basis of how compound 27 inhibits mature CA assembly is rationalized using high-resolution structural information. Our understanding of how compound 27 may inhibit immature Gag assembly is also discussed.     

Novel,potent, selective,and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

We identified a series of structurally novel SCD (Δ9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC₅₀ value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Δ5 and Δ6 desaturases.     

Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors

Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC₅₀ value of 0.41 ± 0.03 μM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies.     

Structure-based design and discovery of potent and selective KDM5 inhibitors

Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1.     

2,4-Diamino-quinazolines as inhibitors of β-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer

The synthesis and SAR of a series of 2,4-diamino-quinazoline derivatives as β-catenin/Tcf-4 inhibitors are described. This series was developed by modifying the initial lead 1, which was identified by screening of our compound library and found to inhibit the β-catenin/Tcf-4 pathway. Replacement of the biphenyl moiety in compound 1 with the N-phenylpiperidine-4-carboxamide chain as in 2, resulted in a number of new analogues, which are potent inhibitors of the β-catenin/Tcf-4 pathway. Compound such as 16k exhibited good cellular potency, solubility, metabolic stability and oral bioavailability.     

Discovery of chiral dihydropyridopyrimidinones as potent,selective and orally bioavailable inhibitors of AKT

During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK₂. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.     

Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide,a highly potent,selective, and orally efficacious factor Xa inhibitor

Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.     

Design,synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors

A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compound 1 with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compounds were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compound 19a, a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo.     

Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases

Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC₅₀ of 4.5 mg/kg.     

2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives,a novel class of SENP1 inhibitors: Virtual screening,synthesis and biological evaluation

Prostate cancer is one of the most prevalent types of malignant cancers in men and has a high mortality rate among all male cancers. Previous studies have demonstrated that Sentrin/SUMO-specific protease 1 (SENP1) plays an important role in the occurrence and development of prostate cancer, and has been identified as a novel drug target for development of small molecule drugs against prostate cancer. In this paper, we used virtual screening and docking to identify compound J5 as a novel lead compound inhibiting SENP1, from SPECS library. We further investigated the SAR (structure–activity relationship) of the benzoate substituent of compound J5, and discovered compounds 8d and 8e as better small molecule inhibitors of SENP1. Both compounds are the high potent SENP1 small molecule inhibitors discovered up to date, and further lead optimization may lead to a series of novel anti-SENP1 agents. Further SAR studies are in process and will be reported in due course.     

Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable EL_HDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.     

Potent,orally bioavailable,liver-selective stearoyl-CoA desaturase (SCD) inhibitors

Two structurally distinct series of SCD (Δ9 desaturase) inhibitors (1 and 2) have been previously reported by our group. In the present work, we merged the structural features of the two series. This led to the discovery of compound 5b (CVT-12,012) which is highly potent in a human cell-based (HEPG2) SCD assay (IC₅₀ = 6 nM). This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times vs plasma) with relatively low brain penetration. In a five-day study (sucrose fed rats) compound 5b significantly reduced SCD activity in a dose-dependent manner as determined by GC analysis of fatty acid composition in plasma and liver, and significantly reduced liver triglycerides versus the control group (～50%).     

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.     

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 1

The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.