Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate.

Bhattacharya, Samit K; Andrews, Kim; Beveridge, Ramsay; Cameron, Kimberly O; Chen, Chiliu; Dunn, Matthew; Fernando, Dilinie; Gao, Hua; Hepworth, David; Jackson, V Margaret; Khot, Vishal; Kong, Jimmy; Kosa, Rachel E; Lapham, Kimberly; Loria, Paula M; Londregan, Allyn T; McClure, Kim F; Orr, Suvi T M; Patel, Jigna; Rose, Colin; Saenz, James; Stock, Ingrid A; Storer, Gregory; VanVolkenburg, Maria; Vrieze, Derek; Wang, Guoqiang; Xiao, Jun; Zhang, Yingxin

Bhattacharya, Samit K; Andrews, Kim; Beveridge, Ramsay; Cameron, Kimberly O; Chen, Chiliu; Dunn, Matthew; Fernando, Dilinie; Gao, Hua; Hepworth, David; Jackson, V Margaret; Khot, Vishal; Kong, Jimmy; Kosa, Rachel E; Lapham, Kimberly; Loria, Paula M; Londregan, Allyn T; McClure, Kim F; Orr, Suvi T M; Patel, Jigna; Rose, Colin; Saenz, James; Stock, Ingrid A; Storer, Gregory; VanVolkenburg, Maria; Vrieze, Derek; Wang, Guoqiang; Xiao, Jun; Zhang, Yingxin.

Afiliación

Bhattacharya SK; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Andrews K; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Beveridge R; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Cameron KO; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Chen C; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Dunn M; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Fernando D; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Gao H; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Hepworth D; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Jackson VM; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Khot V; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Kong J; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Kosa RE; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Lapham K; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Loria PM; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Londregan AT; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
McClure KF; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Orr ST; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Patel J; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Rose C; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Saenz J; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Stock IA; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Storer G; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
VanVolkenburg M; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Vrieze D; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Wang G; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Xiao J; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
Zhang Y; Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, Pharmacokinetics, Dynamics, and Metabolism, Primary Pharmacology Group, and Pharmaceutical Sciences, Pfizer Global Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.

ACS Med Chem Lett ; 5(5): 474-9, 2014 May 08.

Article en En | MEDLINE | ID: mdl-24900864

ABSTRACT

ABSTRACT

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

Palabras clave

Ghrelin; PF-5190457; diabetes; ghrelin receptor antagonist; ghrelin receptor inverse agonist

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