Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis,Journal of Medicinal Chemistry

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Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-30 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01102
Elizabeth J. Curiel Tejeda ₁ , Angelica M. Bello _{1,

2} , Ewa Wasilewski _{1,

2} , Adam Koebel _{1,

2} , Shannon Dunn _{2,

3} , Lakshmi P. Kotra _{1,

2,

4}

Affiliation

Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid-based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential noncovalent inhibitors of PAD enzymes. Among the various heterocycles investigated, compound 23, carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the C_max to be 12.0 ± 2.5 and 170 ± 10 ng/mL in the serum and brain, respectively, when compound 23 was administered at 50 mg/kg via single dose ip. At the same dose, compound 23 also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS.

中文翻译：

非共价蛋白精氨酸脱亚氨酶（PAD）抑制剂在多发性硬化症的动物模型中有效。

肽精氨酸脱亚氨酶已被证明在包括多发性硬化症在内的神经退行性疾病中活跃。合成了基于乙内酰脲核心的，基于α-氨基酸的核心结构，在侧链上具有独特的杂环作为PAD酶的潜在非共价抑制剂。在研究的各种杂环中，带有咪唑部分的化合物23在该系列中显示出最高的效能，并对PAD2具有一定的选择性，并在体内进行了进一步研究。小鼠的药代动力学表明，当通过单剂量腹膜内注射以50 mg / kg的剂量施用化合物23时，血清和大脑中的C _max分别为12.0±2.5和170±10 ng / mL 。在相同剂量下，化合物23在多发性硬化症（MS）的EAE小鼠模型中，他还逆转了身体残疾并清除了T细胞浸润的大脑。这一系列新颖的化合物显示出有望作为疾病改良剂用于MS潜在治疗的进一步发展。

更新日期：2017-10-30

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