Rapid hit to lead evaluation of pyrazolo[3,4-d]pyrimidin-4-one as selective and orally bioavailable mGluR1 antagonists |
| |
| Authors: | Wang Xueqing Kolasa Teodozyi El Kouhen Odile F Chovan Linda E Black-Shaefer Candace L Wagenaar Frank L Garton Jennifer A Moreland Robert B Honore Prisca Lau Yau Yi Dandliker Peter J Brioni Jorge D Stewart Andrew O |
| |
| Affiliation: | Neuroscience Research, Global Pharmaceutical Research and Development, AP9A/L16, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL, USA. xueqing.wang@abbott.com |
| |
| Abstract: | Our HTS effort yielded a preferential mGluR1 pyrimidinone antagonist 1 with lead-like characteristics. Rapid hit to lead (HTL) study identified compounds with improved functional activity and selectivity such as 1b with little improvements in ADME properties. Addition of an aminosulfonyl group on the N-1 aromatic ring led to 2f, a compound with similar in vitro biochemical profiles as those of 1b but drastically improved in vitro ADME properties. These improvements were paralleled by rat PK study characterized by low clearance and quantitative bioavailability. Compound 2f represented a true lead-like molecule that is amenable for further lead optimization (LO) evaluation. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ |
|
