Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead
| Autor: | Motoyuki Tanaka, Taku Fujimoto, Hiromu Habashita, Shinji Nakade, Hideyuki Ueda, Takuya Seko, Yoshikazu Takaoka, Hiroshi Saga, Hiroshi Kohno, Kazuya Hashimura, Hidehiro Suzuki, Masahiko Terakado |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Chemistry Organic Chemistry Antagonist Hit to lead Pharmacology Biochemistry 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Endocrinology Blood pressure In vivo Tamsulosin 030220 oncology & carcinogenesis Internal medicine Drug Discovery Lysophosphatidic acid medicine Potency Receptor medicine.drug |
| Popis: | Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1–6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy. |
| Databáze: | OpenAIRE |
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