title: Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. Electronic address: thomas.graham@merck.com.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Graham
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Garcia-Calvo
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of In Vitro Sciences, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: JeanMarie
authors.initials: J
authors.lastname: Lisnock
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Tung
authors.affiliation: Department of In Vitro Sciences, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Judyann
authors.initials: J
authors.lastname: Wiltsie
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.affiliation: Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
mesh_terms: D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase
keywords: Amide; Angiotensinase C; Enzyme inhibitor; Non-classical bioisostere; Prolylcarboxypeptidase (PrCP); Pyrazole