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Groton, CT, United States

Bhattacharya S.K.,Worldwide Medicinal Chemistry | Andrews K.,Cardiovascular and Metabolic Research Unit | Beveridge R.,Worldwide Medicinal Chemistry | Cameron K.O.,Worldwide Medicinal Chemistry | And 24 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

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. © 2014 American Chemical Society.

Kung D.W.,Worldwide Medicinal Chemistry | Griffith D.A.,Worldwide Medicinal Chemistry | Esler W.P.,Metabolic and Endocrine Diseases Research Unit | Vajdos F.F.,Structural Biology | And 19 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 μM. © 2015 Elsevier Ltd. All rights reserved.

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