Caprolactams as potent CGRP receptor antagonists for the treatment of migraine

Shaw, A.; Paone, Daniel V.; Nguyen, Diem N.; Stump, Craig A.; Burgey, Christopher S.; Mosser, Scott D.; Salvatore, Christopher; Rutledge, Ruth Z.; Kane, Stefanie A.; Koblan, Kenneth S.; Graham, Samuel; Vacca, Joe P.; Williams, Theresa M.

doi:10.1016/j.bmcl.2007.06.062

Cited by 36 publications

(20 citation statements)

References 12 publications

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“…Caprolactam is a lactam of caproic acid (aka hexanoic acid; PubChem Compound Database, CID = 8892; Kim et al, 2016), which is a saturated medium chain fatty acid derived from hexane and found in plants and animal fats. Interestingly, caprolactam is a potent anti-calcitonin gene-related peptide (CGRP) receptor antagonist (Shaw et al, 2007). Calcitonin gene-related peptide, classified as a neuropeptide, has both metabolic as well as reproductive effects.…”

Section: Discussionmentioning

confidence: 99%

Non-targeted Plasma Metabolome of Early and Late Lactation Gilts

Rempel

Miles

Oliver

et al. 2016

Front. Mol. Biosci.

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Female pigs nursing their first litter (first-parity gilts) have increased energy requirements not only to support their piglets, but they themselves are still maturing. Non-targeted plasma metabolomics were used to investigate the differences between (1) post-farrowing and weaning (early or late lactation), (2) degree of body condition loss after lactation (extreme or minimal), and (3) interactions; to potentially identify compounds or pathways that could aide in alleviating energetic demands of lactation in gilts. Twenty first-parity gilts were selected with similar (P ≥ 0.4475) number of piglets born and nursed, and similar (P ≥ 0.3141) body condition traits (e.g., body weight and backfat thickness) post-farrowing, yet exhibited minimal or extreme loss (P ≤ 0.0094) in body weight (8.6 ± 1.48 kg and 26.1 ± 1.90 kg, respectively) and backfat thickness (1.3 ± 0.67 mm and 4.7 ± 0.86 mm, respectively) following lactation (weaning). Plasma samples from first-parity gilts at post-farrowing and weaning were investigated using UPLC-MS and GC-MS to generate a comprehensive metabolic profile. Each approach yielded approximately 700 detected features. An ANOVA was performed on each detected compound in R for time of collection, body condition change, and the interaction, followed by a false discovery correction. Two unknown features were different (P ≤ 0.05) for extreme vs. minimal body condition change. Several compound differences (P ≤ 0.05) were identified between post-farrowing and weaning. Thirty-two features detected by UPLC-MS had at least a log2 fold-change of ±1.0 while only 18 features had a log2 fold-change of ±0.6 or more for the significant GC-MS features. Annotation implicated various metabolic pathways. Creatinine was greater at weaning (P = 0.0224) and others have reported increased serum concentrations of creatinine in response to body weight loss. Hippurate and caprolactam, associated with protein catabolism, were also greater (P ≤ 0.0166) at weaning. Phospholipid features (P ≤ 0.0347) and inositol-related features (P ≤ 0.0236) were also greater at weaning. Inositol features may exert insulin-like effects. The energetic demands of lactation in gilts nursing their first litter indicated a greater difference exists between early and late lactation regardless of body condition loss.

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Section: Discussionmentioning

confidence: 99%

Non-targeted Plasma Metabolome of Early and Late Lactation Gilts

Rempel

Miles

Oliver

et al. 2016

Front. Mol. Biosci.

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“…Fortunately, much SAR work has been published, which allows a retrospective analysis of compound potency as it relates to the key structural features of the CLR/RAMP1 ectodomain complex. Specifically, increases in potency found for compounds on the optimization path to olcegepant (Rudolf et al, 2005) ( Figure 6A) and telcagepant (Paone et al, 2007;Shaw et al, 2007) ( Figure 6B) can be rationalized based on the quality of interactions of the small molecule with pharmacophore recognition sites on CLR/RAMP1. In the case of olcegepant, compounds were selected to optimize electrostatic interactions with the hydrogen bond donoracceptor site at CLR Thr122, while for telcagepant, altering the positioning and stereochemistry of substituents on the caprolactam ring resulted in increased potency through better access to the RAMP1 hydrophobic pocket.…”

Section: Utility Of the Clr/ramp1 Ectodomain Structure For Ligand Designmentioning

confidence: 99%

Section: Utility Of the Clr/ramp1 Ectodomain Structure For Ligand Designmentioning

confidence: 99%

“…Several papers describe the evolution of the caprolactam class of CGRP antagonists leading to the clinical compound telcagepant (Paone et al, 2007;Shaw et al, 2007). The first study (Shaw et al, 2007) describes optimization of the stereochemistry and substitution pattern on the central caprolactam group. Specifically, the hydrogen bond donor-acceptor group was limited to quinazolinone (as found in olcegepant), and the stereochemistry and position of the phenyl group on the seven-membered 1-cyclopropylmethyl caprolactam ring were then modified.…”

Section: Utility Of the Clr/ramp1 Ectodomain Structure For Ligand Designmentioning

confidence: 99%

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Crystal Structure of the Ectodomain Complex of the CGRP Receptor, a Class-B GPCR, Reveals the Site of Drug Antagonism

et al. 2010

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Dysregulation of the calcitonin gene-related peptide (CGRP), a potent vasodilator, is directly implicated in the pathogenesis of migraine. CGRP binds to and signals through the CGRP receptor (CGRP-R), a heterodimer containing the calcitonin receptor-like receptor (CLR), a class B GPCR, and RAMP1, a receptor activity-modifying protein. We have solved the crystal structure of the CLR/RAMP1 N-terminal ectodomain heterodimer, revealing how RAMPs bind to and potentially modulate the activities of the CLR GPCR subfamily. We also report the structures of CLR/RAMP1 in complex with the clinical receptor antagonists olcegepant (BIBN4096BS) and telcagepant (MK0974). Both drugs act by blocking access to the peptide-binding cleft at the interface of CLR and RAMP1. These structures illustrate, for the first time, how small molecules bind to and modulate the activity of a class B GPCR, and highlight the challenges of designing potent receptor antagonists for the treatment of migraine and other class B GPCR-related diseases.

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“…Imidazolin-2-ones have utility as antitumor agents, 4 antibacterial MurB inhibitors, 5 dopamine D 4 and CGRP receptor antagonists, 6,7 antioxidants, 8 and unnatural base pairs. 9 To the best of our knowledge, however, the synthesis and biological evaluation of N -amino-imidazolin-2-ones had not been explored.…”

mentioning

confidence: 99%