Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitors

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• 作者：Thomas H. Graham^a ; ^{thomas.graham@merck.com" class="auth_mail} ; Min Shu^a ; Andreas Verras^a ; Qing Chen^c ; Margarita Garcia-Calvo^b ; Xiaohua Li^c ; JeanMarie Lisnock^d ; Xinchun Tong^c ; Elaine C. Tung^c ; Judyann Wiltsie^d ; Jeffrey J. Hale^a ; Shirly Pinto^b ; Dong-Ming Shen^a
• 关键词：Non-classical bioisostere ; Pyrazole ; Amide ; Enzyme inhibitor ; Prolylcarboxypeptidase (PrCP) ; Angiotensinase C
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 April, 2014
• 年：2014
• 卷：24
• 期：7
• 页码：1657-1660
• 全文大小：1944 K

文摘

Bioisosteres are integral components of modern pharmaceutical research that allow structural optimization to maximize in vivo efficacy and minimize adverse effects by selectively modifying pharmacodynamic, pharmacokinetic and physicochemical properties. A recent medicinal chemistry campaign focused on identifying small molecule inhibitors of prolylcarboxypeptidase (PrCP) initiated an investigation into the use of pyrazoles as bioisosteres for amides. The results indicate that pyrazoles are suitable bioisosteric replacements of amide functional groups. The study is an example of managing bioisosteric replacement by incorporating subsequent structural modifications to maintain potency against the selected target. A heuristic model for an embedded pharmacophore is also described.