Synthesis and biological evaluation of novel quinazoline-4-piperidinesulfamide derivatives as inhibitors of NPP1.

The ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) was recently shown to promote mineralization of the aortic valve, hence, its inhibition represents a significant target. A quinazoline-4-piperidine sulfamide compound (QPS1) has been described as a specific and non-competitive inhibitor of NPP1. We report herein the synthesis and in vitro inhibition studies of novel quinazoline-4-piperidine sulfamide analogues using QPS1 as the lead compound. Of the 26 derivatives prepared, four compounds were found to have Ki < 105 nM against human NPP1.

Synthesis of novel substituted pyrimidine derivatives bearing a sulfamide group and their in vitro cancer growth inhibition activity.

The synthesis of two series of novel substituted pyrimidine derivatives bearing a sulfamide group have been described and their in vitro cancer growth inhibition activities have been evaluated against three human tumour cell lines (HT-29, M21, and MCF7). In general, growth inhibition activity has been enhanced by the introduction of a bulky substituent on the aromatic ring with the best compound having GI50<6µM for all the human tumour cell lines. The MCF7 selective compounds were evaluated on four additional human invasive breast ductal carcinoma cell lines (MDA-MB-231, MDA-MB-468, SKBR3, and T47D) and were selective against T47D cell line in all cases except one, suggesting a potential antiestrogen activity.

Quinazoline-4-piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells.

BACKGROUND AND PURPOSE: Ectonucleotide pyrophosphatase/PDE1 (NPP1) is an ectoenzyme, which plays a role in several disorders including calcific aortic valve disease (CAVD). So far, compounds that have been developed as inhibitors of NPP1 lack potency and specificity. Quinazoline-4-piperidine sulfamides (QPS) have been described as potent inhibitors of NPP1. However, their mode of inhibition as well as their selectivity and capacity to modify biological processes have not been investigated. EXPERIMENTAL APPROACH: In the present series of experiments, we have evaluated the efficacy of two derivatives, QPS1-2, in inhibiting human NPP1, and we have evaluated the effect of the most potent derivative (QPS1) on other ectonucleotidases as well as on the ability of this compound to prevent phosphate-induced mineralization of human primary aortic valve interstitial cells (VICs). KEY RESULTS: The QPS1 derivative is a potent (Ki 59.3 ± 5.4 nM) and selective non-competitive inhibitor of human NPP1. Moreover, QPS1 also significantly inhibited the K121Q NPP1 gene variant (Ki 59.2 ± 14.5 nM), which is prevalent in the general population. QPS1 did not significantly alter the activity of other nucleotide metabolizing ectoenzymes expressed at the cell surface, namely NPP3, NTPDases (1-3), ecto-5'-nucleotidase and ALP. Importantly, QPS1 in the low micromolar range (≤10 µM) prevented phosphate-induced mineralization of VICs and lowered the rise of osteogenic genes as expected for NPP1 inhibition. CONCLUSIONS AND IMPLICATIONS: We have provided evidence that QPS1 is a potent and selective non-competitive inhibitor of NPP1 and that it prevented pathological mineralization in a cellular model.

Synthesis and pharmacological evaluation of a new series of radiolabeled ligands for 5-HT7 receptor PET neuroimaging.

INTRODUCTION: The brain serotonin-7 receptor (5-HT7) is the most recently discovered serotonin receptor. It is targeted by several drug-candidates in psychopharmacology and neuropharmacology. In these fields, positron emission tomography (PET) is a molecular imaging modality offering great promise for accelerating the development process from preclinical discovery to clinical phases. We recently described fluorinated 5-HT7 radioligands, inspired by the structure of SB269970, the prototypical 5-HT7 antagonist. Although these results were promising, it appeared that the radiotracer-candidates suffered, among other drawbacks, from too low a 5-HT7 receptor affinity. METHODS: In the present study, seven structural analogs of SB269970 were synthesized using design strategies aiming to improve their radiopharmacological properties. Their 5-HT7 binding properties were investigated by cellular functional assay. The nitro-precursors of the analogs were radiolabeled by [(18)F-]nucleophilic substitution, and in vitro autoradiography was performed in rat brain, followed by in vivo microPET. RESULT: The chemical and radiochemical purity of the fluorine radiotracers was>99% with specific activity in the 40-129GBq/µmol range. The seven derivatives presented heterogeneous binding affinities toward 5-HT7 and 5-HT1A receptors. While [(18)F]2F3P3 had promising characteristics in vitro, it showed poor brain penetration in vivo, partially reversed after pharmacological inhibition of P-glycoprotein. CONCLUSIONS: These results indicated that, while chemical modification of these series improved several radiotracer-candidates in terms of 5-HT7 receptor affinity and specificity toward 5-HT1A receptors, other physicochemical modulations would be required in order to increase brain penetration.