title: Evaluation and synthesis of polar aryl- and heteroaryl spiroazetidine-piperidine acetamides as ghrelin inverse agonists.
abstract: Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Suvi T M
authors.initials: ST
authors.lastname: Orr
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Ramsay
authors.initials: R
authors.lastname: Beveridge
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 610 Main St., Cambridge, Massachusetts 02139, United States.
authors.forename: Samit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 610 Main St., Cambridge, Massachusetts 02139, United States.
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: Cameron
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Coffey
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Dilinie
authors.initials: D
authors.lastname: Fernando
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 610 Main St., Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Cardiovascular and Metabolic Research Unit, Pfizer Global Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Jackson
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Vishal
authors.initials: V
authors.lastname: Khot
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kosa
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lapham
authors.affiliation: Primary Pharmacology Group, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 610 Main St., Cambridge, Massachusetts 02139, United States.
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
authors.affiliation: Pharmaceutical Sciences, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jigna
authors.initials: J
authors.lastname: Patel
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 610 Main St., Cambridge, Massachusetts 02139, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Rose
authors.affiliation: Pharmaceutical Sciences, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: James
authors.initials: J
authors.lastname: Saenz
authors.affiliation: Primary Pharmacology Group, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Stock
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Storer
authors.affiliation: Cardiovascular and Metabolic Research Unit, Pfizer Global Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: von Volkenburg
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Vrieze
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 550 Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhang
keywords: Heteroaryl acetic acid; carboxamide; ghrelin; growth hormone secretagogue receptor 1a; spiroazetidine-piperidine; type 2 diabetes