Rapid hit to lead evaluation of pyrazolo[3,4-d]pyrimidin-4-one as selective and orally bioavailable mGluR1 antagonists
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- 作者：Xueqing Wang ; Teodozyi Kolasa ; Odile F. El Kouhen ; Linda E. Chovan ; C ; ace L. Black-Shaefer ; Frank L. Wagenaar ; Jennifer A. Garton ; Robert B. Morel ; Prisca Honore ; Yau Yi Lau ; Peter J. D ; liker ; Jorge
- 关键词：mGluR1 antagonist ; Hit to lead ; ADME
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2007
- 出版时间：1 August 2007
- 年：2007
- 卷：17
- 期：15
- 页码：4303-4307
- 全文大小：154 K
文摘
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.