Discovery and Characterization of RGH-122, a Potent, Selective, and Orally Bioavailable V1a Receptor Antagonist

被引：2

作者：

Baska, Ferenc ^{[1
]}

Bozo, Eva ^{[1
]}

Szeleczky, Zsolt ^{[1
]}

Szanto, Gabor ^{[1
]}

Vukics, Krisztina ^{[1
]}

Szakacs, Zoltan ^{[1
]}

Domany-Kovacs, Katalin ^{[1
]}

Kurko, Dalma ^{[1
]}

Vass, Elemer ^{[2
]}

Than, Marta ^{[1
]}

Vastag, Monika ^{[1
]}

Temesvari, Krisztina ^{[1
]}

Levai, Sandor ^{[1
]}

Halasz, Attila Sandor ^{[1
]}

Kordas, Krisztina Szondine ^{[1
]}

Roman, Viktor ^{[1
]}

Greiner, Istvan ^{[1
]}

Bata, Imre ^{[1
]}

机构：

[1] Gedeon Richter Plc, H-1475 Budapest, Hungary

[2] Eotvos Lorand Univ, Inst Chem, H-1117 Budapest, Hungary

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 01期

关键词：

RANDOMIZED CONTROLLED-TRIAL; AUTISM SPECTRUM DISORDERS; VASOPRESSIN V1A; ACTIVE METABOLITE; BALOVAPTAN; PHARMACOKINETICS; PAZINACLONE; INHIBITION; SR-49059; SINGLE;

D O I：

10.1021/acs.jmedchem.3c01868

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved in vitro and in vivo profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound 43 (RGH-122). The CNS activity of the compound was determined in a 3-chamber social preference test of autism in which RGH-122 successfully enhanced social preference with the lowest effective dose of 1.5 mg/kg.

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收藏

页码：643 / 673

页数：31

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