Discovery of potent, cyclic calcitonin gene‐related peptide receptor antagonists

Abstract

Calcitonin gene-related peptide (CGRP), a potent dilator of cerebral and dural vasculature, is known to be elevated in plasma and cerebral spinal fluid during migraine attacks. Selective blockade of the CGRP receptor offers the promise of controlling migraine headache more effectively and without the side-effects associated with the use of triptans. Our efforts to develop a novel, peptide-based CGRP antagonist focused on the C-terminal portion of the peptide which is known to bind the receptor but lack agonist properties. Extensive SAR studies of the C-terminal CGRP (27-37) region identified a novel cyclic structure: Bz-Val-Tyr-cyclo[Cys-Thr-Asp-Val-Gly-Pro-Phe-Cys]-Phe-NH(2) (23) with a kb value of 0.126 nM against the cloned human CGRP receptor. Additional SAR studies directed at enhancement of potency and improvement of physicochemical properties yielded a series of analogs with kb values in the 0.05-0.10 nM range.

Structure–activity relationships for α‐calcitonin gene‐related peptide

“…However, as with amino acid substitutions, the details of the effects depend on the analogue. A bridge between residues 31 and 36 is well tolerated for CGRP8-37 but not in a CGRP27-37 derivative, where only a 29-36 bridge was effective (Heino et al, 1998;Yan et al, 2011).…”

“…P. bicolor CGRP naturally contains many of the substitutions that are used to increase the affinity of human α‐CGRP 27–37 (Figure ). In some studies, constraints have been introduced such as with a disulphide bond, or others have used amino acid substitutions to promote bends, either in fragments or full‐length CGRP (Hakala et al ., ; Heino et al ., ; Rist et al ., ; ; Wisskirchen et al ., ; Carpenter et al ., ; Lang et al ., ; Boeglin et al ., ; Yan et al ., ) ( Table , Figure ). The most significant residues seem to be in the 30–37 segment of peptide, but with a turn, around residue 29 being important to orientate Thr 30 (Carpenter et al ., ; Lang et al ., ).…”

“…P. bicolor CGRP naturally contains many of the substitutions that are used to increase the affinity of human a-CGRP27-37 (Figure 1). In some studies, constraints have been introduced such as with a disulphide bond, or others have used amino acid substitutions to promote bends, either in fragments or full-length CGRP (Hakala et al, 1994;Heino et al, 1998;Rist et al, 1998;Wisskirchen et al, 2000;Carpenter et al, 2001;Lang et al, 2006;Boeglin et al, 2007;Yan et al, 2011) (Table 4, Figure 5). The most significant residues seem to be in the 30-37 segment of peptide, but with a turn, around residue 29 being important to orientate Thr 30 (Carpenter et al, 2001; No decrease in affinity Rat pulmonary artery (Wisskirchen et al, 2000) Gly 20 [Gly 20 ]-CGRP8-37 Twofold decrease in affinity Guinea pig atrium (Boulanger et al, 1996) Residues 1-18 CGRP19-37 40-fold decrease in affinity SK-N-MC cells (Poyner et al, 1998) Residues 1-7 and 19-27 CGRP8-18, 28-37 18-fold decrease in affinity SK-N-MC cells (Poyner et al, 1998) Residues 1-27 Tyr 0 -CGRP28-37 170-fold decrease in affinity (fourfold decrease with respect to CGRP19-37) SK-N-MC cells (Poyner et al, 1998) All differences are with respect to human a-CGRP8-37.…”

“…By contrast, Tyr substitution is not tolerated in Tyr 0 -CGRP28-37 (Rist et al, 1999). In a disulphideconstrained analogue, Phe 37 can be replaced by pyridylalanine (Yan et al, 2011). There is agreement that the C-terminal amide is essential for all analogues (Rist et al, 1999;Smith et al, 2003).…”

“…These were initially based on peptide fragments lacking the N-terminal disulphide-bonded loop, of which the best characterized is CGRP8-37 (Chiba et al, 1989;Dennis et al, 1990). More recently, attention has focused on shorter peptides, which are often derivatives of CGRP27-37 (Yan et al, 2011). The non-peptide antagonists are typified by olcegepant and telcagepant (Negro et al, 2012).…”