Phenyl(thio)phosphon(amid)ate Benzenesulfonamides as Potent and Selective Inhibitors of Human Carbonic Anhydrases II and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced Neuropathy

被引：23

作者：

Nocentini, Alessio ^{[2
]}

Alterio, Vincenzo ^{[1
]}

Bua, Silvia ^{[2
]}

Micheli, Laura ^{[3
]}

Esposito, Davide ^{[1
]}

Buonanno, Martina ^{[1
]}

Bartolucci, Gianluca ^{[2
]}

Osman, Sameh M. ^{[4
]}

ALOthman, Zeid A. ^{[4
]}

Cirilli, Roberto ^{[5
]}

Pierini, Marco ^{[6
]}

Monti, Simona Maria ^{[1
]}

Mannelli, Lorenzo Di Cesare ^{[3
]}

Gratteri, Paola ^{[2
]}

Ghelardini, Carla ^{[3
]}

De Simone, Giuseppina ^{[1
]}

Supuran, Claudiu T. ^{[2
]}

机构：

[1] CNR, Ist Biostrutture & Bioimmagini, I-80134 Naples, Italy

[2] Univ Florence, Dept NEUROFARBA, Pharmaceut & Nutraceut Sect, I-50019 Sesto Fiorentino, Italy

[3] Univ Florence, Dept NEUROFARBA, Pharmacol & Toxicol Sect, I-50139 Florence, Italy

[4] King Saud Univ, Coll Sci, Chem Dept, Riyadh 11451, Saudi Arabia

[5] Ist Super Sanita, Ctr Nazl Controllo & Valutaz Farm, I-00161 Rome, Italy

[6] Sapienza Univ Rome, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 10期

关键词：

NOCICEPTIN/ORPHANIN FQ RECEPTOR; CRYSTAL-STRUCTURE; CHRONIC PAIN; STRATEGY; ERRORS; BRAIN;

D O I：

10.1021/acs.jmedchem.9b02135

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.

引用

页码：5185 / 5200

页数：16