The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor

Westaway, Susan M.; Brown, Samantha; Conway, Elizabeth A.; Heightman, Tom D.; Johnson, Christopher N.; Lapsley, Kate; Macdonald, Gregor; MacPherson, David T.; Mitchell, Darren J.; Myatt, James W.; Seal, Jon T.; Stanway, Steven J.; Stemp, Geoffrey; Thompson, Mervyn; Celestini, Paolo; Colombo, Andrea; Consonni, Alessandra; Gagliardi, Stefania; Riccaboni, Mauro; Ronzoni, Silvano; Briggs, Michael A.; Matthews, Kim L.; Stevens, Alexander J.; Bolton, Victoria J.; Boyfield, Izzy; Jarvie, Emma M.; Stratton, Sharon C.; Sanger, Gareth J.

doi:10.1016/j.bmcl.2008.10.072

Cited by 11 publications

(14 citation statements)

References 27 publications

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“…Several TRPV1 antagonists of the carboxamide type have been discovered. These compounds show IC 50 values in the 10 to 100 nM range and are structurally quite heterogenous, as exemplified by comparison of the nicotinamide derivative SB-782443 (36), the thiazolylcarboxamide (37), and the tetrahydropyridylcarboxamide (38) (Westaway et al, 2008a) (Table 2). SB-782443 (36) showed excellent potency at human, guinea pig, and rat TRPV1, a favorable in vitro Drug Metabolism and Pharmacokinetics profile, and remarkable in vivo activity in an inflammatory pain model (Westaway et al, 2006;Brown et al, 2008).…”

Section: Trpv1 Antagonistsmentioning

confidence: 99%

“…SB-782443 (36) showed excellent potency at human, guinea pig, and rat TRPV1, a favorable in vitro Drug Metabolism and Pharmacokinetics profile, and remarkable in vivo activity in an inflammatory pain model (Westaway et al, 2006;Brown et al, 2008). Based on their in vitro profile, several compounds of this class qualified for preclinical development (Westaway et al, 2008a).…”

Section: Trpv1 Antagonistsmentioning

confidence: 99%

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Pharmacology of Vanilloid Transient Receptor Potential Cation Channels

Vriens

Appendino²,

Nilius³

2009

Mol Pharmacol

383

352

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Section: Trpv1 Antagonistsmentioning

confidence: 99%

Section: Trpv1 Antagonistsmentioning

confidence: 99%

Pharmacology of Vanilloid Transient Receptor Potential Cation Channels

Vriens

Appendino²,

Nilius³

2009

Mol Pharmacol

383

352

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“…1). More recently, the benzylpiperazine structure has been discovered as a useful template for the preparation of motilin agonists 22,23 . In this study, we describe the pharmacology of one of these compounds, namely GSK962040 (Fig.…”

Section: Introductionmentioning

confidence: 99%

GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility

Sanger

Westaway

Barnes

et al. 2009

Neurogastroenterology Motil

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There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5-hydroxytryptamine type 4 receptor agonist and an antagonist at brain D2 receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC50 (the negative logarithm to base 10 of the EC50 value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L(-1)-10 micromol L(-1) caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 +/- 47% at 3 micromol L(-1). In human-isolated stomach, GSK962040 10 micromol L(-1), erythromycin 10 micromol L(-1) and [Nle13]-motilin 100 nmol L(-1), each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg(-1) GSK962040 or 10 mg kg(-1) erythromycin significantly increased faecal output over a 2-h period. Together, these data show that GSK962040, a non-motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.

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“…Camicinal is a motilin receptor agonist of a novel chemical class. It has a short half‐life and did not show any signs of desensitization of its gastric motility stimulating efficacy after 14 days of treatment in healthy controls . In the present study, both 50 and 150 mg of camicinal were well‐tolerated and the highest dose induced significant stimulation of interdigestive upper gastrointestinal contractility patterns.…”

Section: Discussionmentioning

confidence: 42%

“…Hence, there is a clear need for new drugs for the treatment of gastroparesis and functional dyspepsia with delayed gastric emptying. Recently, a new class of motilin receptor agonists, derived from a benzylpiperazine molecular structure, was identified . It has already been shown that camicinal (GSK962040), one of these agents, selectively activates the recombinant human motilin receptor, induces contractions in human and rabbit isolated stomach preparations and increases the fecal output in conscious rabbits .…”

Section: Introductionmentioning

confidence: 99%