Novel CGRP receptor antagonists through a design strategy of target simplification with addition of molecular flexibility

Wood, Michael R.; Schirripa, Kathy M.; Kim, June J.; Quigley, Amy G.; Stump, Craig A.; Bell, Ian M.; Bednar, Rodney A.; Fay, John F.; Bruno, Joseph G.; Moore, Eric L.; Mosser, Scott D.; Roller, Shane; Salvatore, Christopher; Kane, Stefanie A.; Vacca, Joseph P.; Selnick, Harold G.

doi:10.1016/j.bmcl.2009.07.134

Cited by 13 publications

(17 citation statements)

References 10 publications

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“…The majority of CGRP receptor small molecule antagonists showed minimal or no activity against AM 1 and AM 2 receptors . However, a search of the literature highlighted two CGRP receptor antagonists with encouraging activity against AM 2 receptor–compounds 3 (MK-3207) and 2 (pIC 50 = 6.20 and 5.97 respectively for AM 2 receptor respectively, determined in house). Comparison with the chemical structure of the more selective CGRP antagonist telcagepant ( 1 ) allowed us to highlight areas of each molecule which bind to CLR (blue) and RAMP (red) proteins (Figure c).…”

Section: Resultsmentioning

confidence: 99%

Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor

Avgoustou

Jailani

Zirimwabagabo

et al. 2020

ACS Pharmacol. Transl. Sci.

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The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in the regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumor progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). The CLR with RAMP2 forms an adrenomedullin-1 receptor, and the CLR with RAMP3 forms an adrenomedullin-2 receptor. Recent research suggests that a selective blockade of adrenomedullin-2 receptors would be therapeutically valuable. Here we describe the design, synthesis, and characterization of potent small-molecule adrenomedullin-2 receptor antagonists with 1000-fold selectivity over the adrenomedullin-1 receptor, although retaining activity against the CGRP receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties, and inhibit xenograft tumor growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anticancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.

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Section: Resultsmentioning

confidence: 99%

Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor

Avgoustou

Jailani

Zirimwabagabo

et al. 2020

ACS Pharmacol. Transl. Sci.

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“…It had a t ½ of 1.6 h, reflected in the plasma concentrationdependent inhibition of capsaicin-induced vasodilatation [61]. Recently Merck reported several more compounds (including MK-3207) with higher affinity, in vitro and in vivo potency, bioavailability, and considerable structural diversity [62][63][64][65]. MK-3207 had also a slower off-rate of 59 min (t ½ ) compared with 1.3 min for telcagepant [66].…”

Section: Cgrp Receptor Antagonistsmentioning

confidence: 99%

Calcitonin gene-related peptide receptor antagonists for migraine

Fischer

2010

Expert Opinion on Investigational Drugs

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“…Calcitonin gene-related peptide (CGRP) exhibits potent vasodilation activity and is involved in the pathogenesis of migraine 100 . Recent studies revealed that CGRP antagonists could be efficacious and well tolerated in the migraine treatment101, 102. Two small-molecule CGRP receptor antagonists, olcegepant and telcagepant, effectively normalized circulating CGRP levels with concomitant pain relief101, 103.…”

Section: Structural Simplification Of Bioactive Small Moleculesmentioning

confidence: 99%

“…Two small-molecule CGRP receptor antagonists, olcegepant and telcagepant, effectively normalized circulating CGRP levels with concomitant pain relief101, 103. Bell et al 102 . reported a novel class of CGRP inhibitors with high potency ( 76 , K i = 0.13 nmol/L, Fig.…”

Section: Structural Simplification Of Bioactive Small Moleculesmentioning

confidence: 99%

“…To discover novel CGRP receptor antagonists, Selnick et al . 102 performed a systematic step-by-step simplification of 76 . First, the pyridine substructure of 76 was replaced by an amide, which had little impact on the binding affinity, while greatly simplifying the synthetic route as a straightforward amide coupling could then be used.…”

Section: Structural Simplification Of Bioactive Small Moleculesmentioning

confidence: 99%

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Structural simplification: an efficient strategy in lead optimization

Wang

Dong

Sheng

2019

Acta Pharmaceutica Sinica B

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The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding “molecular obesity”. The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

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Novel CGRP receptor antagonists through a design strategy of target simplification with addition of molecular flexibility

Cited by 13 publications

References 10 publications

Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor

Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor

Calcitonin gene-related peptide receptor antagonists for migraine

Structural simplification: an efficient strategy in lead optimization

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