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relationship (SAR) development has been reported. However, the journey
leading to the clinical candidates described herein started with the cinnamide
hit 5. The following discussion will summarize the challenges encountered with
the discovery of AMG 517 as well as the second-generation compound, AMG
628. The key advances in the SAR investigations will be highlighted to illustrate
project milestones that were achieved and selected data will be shown for each
compound. For full details and additional information regarding the complete
SAR development of the compounds in this series, the reader is referred to the
original journal articles referenced herein.
13.3 Identification of a Proof-of-concept Molecule
The initial goal of the project was to identify a proof-of-concept molecule for
evaluation in in vivo models. This was rapidly accomplished by the initial
screening of commercially available cinnamides based on the HTS hit 5. From
this effort we identified N-arylcinnamide 6 as a potent, competitive antagonist
that blocked the capsaicin-, heat-, and pH-induced uptake of
45
Ca
21
in
hTRPV1-expressing CHO cells (Figure 13.3).
49
Schild analysis and electrophysiology experiments indicated that cinnamide 6
was competitive with capsaicin and bound reversibly. Furthermore, compound
6 was shown to be selective against a panel of over 80 other targets, including
various voltage- and ligand-gated ion channels, G-protein-coupled receptors,
and transporters. In vivo, we demonstrated that cinnamide 6 was effective at
preventing a capsaicin-induced eye wiping response in a dose-dependent
manner, as well as reversing thermal hyperalgesia in a model of inflammatory
pain induced by intraplantar injection of complete Freund's adjuvant (CFA) in
rats (Figures 13.4A and 13.4B, respectively).
45
13.4 Lead Optimization
13.4.1 Identification of the Clinical Candidate AMG 517
Although cinnamide 6 served well as a proof-of-concept molecule to support
pursuing TRPV1 antagonists as potential pain therapeutics, it suffered from
Cl
Increased
Potency
N
N
Cl
O
O
Screen
Commercial
Cinnamides
O
O
5
6
hTRPV1(Cap) IC
50
= 1,200 nM
hTRPV1(Cap) IC
50
= 24 nM
hTRPV1(45
C) IC
50
= 16 nM
hTRPV1(pH5.0) IC
50
= 93 nM
°
Figure 13.3
Identification of the proof-of-concept molecule, N-arylcinnamide (6).
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