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The development of selective histone deacetylase 6 inhibitors (sHDAC6is) is being recognized as a therapeutic approach for cancers. In this paper, we designed a series of novel tetrahydropyridopyrimidine derivatives as sHDAC6 inhibitors. The most potent compound, 8-(2, 4-bis(3-methoxyphenyl)-5, 8-dihydropyrido [3, 4-d]pyrimidin-7(6H)-yl)-N-hydroxy-8-oxooctanamide (8f), inhibited HDAC6 with IC50 of 6.4 nM, and showed > 48-fold selectivity over other subtypes. In Western blot assay, 8f elevated the levels of acetylated α-tubulin in a dose-dependent manner. In vitro, 8f inhibited RPMI-8226, HL60, and HCT116 tumor cells with IC50 of 2.8, 3.20, and 3.25 μM, respectively. Moreover, 8f showed good antiproliferative activity against a panel of tumor cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A new series of TLR 7/8 dual agonists based on tetrahydropyridopyrimidines. • A desired high first pass effect was observed to limit systemic exposure and cytokine activation. • Target engagement was demonstrated by the induction of IP-10 after oral administration in mice. Abstract In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure–activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant. [ABSTRACT FROM AUTHOR]

Highlights: [•] Synthesis of tetrahydropyrido-pyrimidines. [•] Acute nociceptive assays performed. [•] Chronic constriction injury and partial sciatic nerve ligation models in animals were used. [•] Quantification of ED50 for potential analogs determined. [•] Mechanistic studies on inflammatory mediation, oxidative and nitrosative stress performed. [ABSTRACT FROM AUTHOR]

Abstract: We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine. [Copyright &y& Elsevier]

Abstract: We report the development of a novel three-component coupling reaction (3CC) for the synthesis of alkoxy tetrahydropyridopyrimidines. Systematic optimization of reaction parameters identified 3CC conditions tolerant of a wide array of functionality at all three sites of diversity, providing densely functionalized products in moderate to excellent yields. The newly developed chemistry has since been applied to the lead optimization process on a novel drug discovery program, facilitating rapid compound advancement. [Copyright &y& Elsevier]

• A series of tetrahydropyridopyrimidine derivatives targeting GPR119 and DPP-4 were designed and synthesized. • Compound 51 was revealed to show both GPR119 agonistic and DPP-4 inhibitory activities. • Compound 51 demonstrated potent hypoglycemic effect compared with vildagliptin. • The 3D binding mode of 51 with DPP-4 was generated. Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC 50 = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 μM. Furthermore, the blood glucose AUC 0-2h of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators. [ABSTRACT FROM AUTHOR]