Abstract
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.
MeSH terms
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Administration, Oral
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Animals
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Crystallography, X-Ray
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Diabetes Mellitus, Type 2 / drug therapy
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Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
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Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
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Dogs
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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Pyrrolidines / chemical synthesis
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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(3,3-difluoropyrrolidin-1-yl)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl)methanone
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Dipeptidyl-Peptidase IV Inhibitors
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Hypoglycemic Agents
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Pyrimidines
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Pyrrolidines