Synthesis of 7-(tetrahydropyran-2-yl)- and 7-(4-acetoxytetrahydropyran-2-yl)-ε-rhodomycinone and 7-(tetrahydropyran-2-yl)-ε-pyrromycinone

The ¹³C.n.m.r spectra of water-soluble and -insoluble glucans synthesized by enzymes isolated from six strains of Streptococcus mutans are interpreted. The glucans are shown to be composed primarily of α(1→3)- and α-(1→6)-linked glucosyl residues, and the relative abundance of each linkage is estimated from peak areas. Treatment of water-insoluble glucans with dextranase is found to result in water-soluble and -insoluble products, the former enriched in α-(1→6)-linkages and the latter in α-(1→3)-linkages. The structural conclusions arrived at by ¹³C-n.m.r. spectroscopy are consistent with data from methylation analysis and ¹H-n.m.r. spectroscopy.     

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 (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel RORγt inverse agonists

A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure–activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC₅₀ of 61 nM in an inverse agonist assay), selective relative to RORα, RORβ, LXRα and LXRβ, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Y_max (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.     

2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-β1 and activin A signalling

Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.     

(S)-3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2-(piperazin-1-yl)propanoic acid compounds: Synthesis and biological evaluation of dual PPARα/γ agonists

A series of novel, potent PPARα/γ dual agonists were synthesized and appraised. The most potent analogue, compound 2b demonstrated EC₅₀ value of 0.012 ± 0.002 and 0.032 ± 0.01 μM, respectively, for hPPARα and hPPARγ in transactivation assay. Additionally, compound 2b demonstrated good glucose and lipid lowering effect in genetic diabetic (db/db) mice.     

Synthesis of 3′-Deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine via 1,3-Dipolar Cycloaddition

Abstract

The synthesis of new 3′-deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine 6a–f, from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine is described. The key step is the 1,3-dipolar cycloaddition between the azido group of the protected AZT 3 and N-1-propargylpyrimidine derivatives 2a–f. All new derivatives 6a–f were evaluated for their inhibitory effects against the replication of HIV-1 (IIIB), HIV-2 (ROD). No marked activity was found.     

Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases

Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure–activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration.     

Identification of biaryl sulfone derivatives as antagonists of the histamine H₃ receptor: discovery of (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916)

The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.     

Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P₁ agonists

S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.     

Design,synthesis and biological activity evaluation of novel 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as potent transforming growth factor-β (TGF-β) type I receptor inhibitors

TGF-β type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. The optimization led to identification of potent and selective ALK5 inhibitors 12r. The compound 12r exhibited strong inhibitory activity both in vitro and in vivo, and pharmacokinetics study showed an oral bioavailability of 57.6%. Thus, compound 12r may provide as new therapeutic option as ALK5 TGF-βR1 inhibitor.     

Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.     

Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles 14a-e, 15a-e, 17a-c, and 18a-d have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 6-quinolinyl pyrazole analogue 14b inhibited ALK5 phosphorylation with IC(50) value of 0.022 μM and showed 84% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.     

Discovery of N-(4′-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication

A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC₅₀ values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC₅₀ = 0.17 μM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3 h and oral bioavailability (F) of 58%.     

6-amino-4-(pyrimidin-4-yl)pyridones: novel glycogen synthase kinase-3β inhibitors

The synthesis and structure-activity relationships for a novel series of 6-amino-4-(pyrimidin-4-yl)pyridones derived from a high throughput screening hit are discussed. Optimization of lead matter afforded compounds with good potency, selectivity and central nervous system (CNS) exposure.     

Synthesis of 3′-Deoxy-3′ and 5′-Deoxy-5′-[4-(Purin-9-yl/Pyrimidin-1-yl) methyl-1,2,3-Triazol-1-yl]thymidine via 1,3-Dipolar Cycloaddition

Abstract

Synthesis of new 3′-deoxy-3′ and 5′-deoxy-5′-[(4-(purin-9-yl/pyrimidin-1-yl)methyl-1,2,3-Triazol-1-yl]thymidine 8a-g 10a-g from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine and 5′-azido-5′deoxythymidine respectively are described. The key step is the 1,3-dipolar cycloaddition between the azido group and N-9/N-1-propargylpurine/pyrimidine derivatives.     

Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3β with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.     

Synthesis and biological evaluation of 4-(piperid-3-yl)amino substituted 6-pyridylquinazolines as potent PI3Kδ inhibitors

PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC₅₀ values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC₅₀ = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kβ and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kβ. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC₅₀ values of 0.16 and 0.12 μM. Western blot analysis indicated that A8 could attenuate the AKT^S473 phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.     

Discovery of N-{N-[(3-cyanobenzene) sulfonyl]-4(R)-(3,3-difluoropiperidin-1-yl)-(l)-prolyl}-4-[(3′,5′-dichloro-isonicotinoyl) amino]-(l)-phenylalanine (MK-0617), a highly potent and orally active VLA-4 antagonist

A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats.