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

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

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.

Keywords: Ghrelin; PF-5190457; diabetes; ghrelin receptor antagonist; ghrelin receptor inverse agonist.

Figures

Figure 1
Figure 1
Examples of ghrelin receptor antagonists.
Figure 2
Figure 2
Comparative CEREP profile of 11 (bottom) and 16h (top).
Scheme 1. Synthesis of Analogues 16a –…
Scheme 1. Synthesis of Analogues 16a–h
Reagents and conditions: (a) (i) HOAc, MeOH, 50 °C, 2 h; (ii) NaCNBH3, 70 °C; 99%; (b) bis(pinacolato)diboron, Pd(dppf)Cl2 (1.6 mol %), KOAc, dioxane, 110 °C, 1 h, >99% conversion; (c) R1-Cl or R1-Br, Pd(dppf)Cl2 (2.5 mol %), K2CO3 (aq), dioxane, 110 °C, 3 h, 90% conversion; (d) HCl; (e) TFA; (f) R2CH2CO2H (14), HBTU or CDI, DIEA or TEA, 50–99% (over 2 steps).
Figure 3
Figure 3
Glucose-stimulated insulin secretion in human whole islet static culture following incubation with 16h at 1 μM. **p < 0.001; *p < 0.05. Measurement data are expressed as the arithmetic mean ± standard error.

Source: PubMed

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