Camicinal hydrochloride

• CAT Number: I005456
• CAS Number: 923565-22-4
• Molecular Formula: C25H34ClFN4O
• Molecular Weight: 461.02
• Purity: ≥95%
• Synonyms: 1-[4-(3-fluoroanilino)piperidin-1-yl]-2-[4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl]ethanone;hydrochloride
• InChI: InChI=1S/C25H33FN4O.ClH/c1-19-17-29(14-11-27-19)18-21-7-5-20(6-8-21)15-25(31)30-12-9-23(10-13-30)28-24-4-2-3-22(26)16-24;/h2-8,16,19,23,27-28H,9-15,17-18H2,1H3;1H/t19-;/m0./s1
• InChIKey: MZEVMNJFEUATKJ-FYZYNONXSA-N
• SMILES: CC1CN(CCN1)CC2=CC=C(C=C2)CC(=O)N3CCC(CC3)NC4=CC(=CC=C4)F.Cl

Camicinal hydrochloride (GSK962040 hydrochloride) is a small molecule, selective motilin receptor agonist with pEC50 of 7.9.
Camicinal hydrochloride (GSK962040 hydrochloride) had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, Camicinal hydrochloride (GSK962040 hydrochloride) 300 nmol L 1-10 μmol L 1 caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 ± 47% at 3 μmol L 1. The pEC50 values for motilin, erythromycin and Camicinal hydrochloride (GSK962040 hydrochloride) were, respectively, 10.4 ± 0.01 (n = 770), 7.3 ± 0.29 (n = 4) and 7.9 ± 0.09 (n = 17) [1]. Camicinal hydrochloride (GSK962040 hydrochloride) activated the dog motilin receptor (pEC50 5.79; intrinsic activity 0.72, compared with [Nle13]-motilin) [2]. Camicinal hydrochloride (GSK962040 hydrochloride) was preferred because its initial IC50 values at CYP3A4 were significantly higher than our preferred threshold of 10 μM [3].
Camicinal (GSK962040) (5 mg free base kg 1) also produced an increase in total faecal weight over the 2-h postdose period (21.2 ± 4.5 g; P < 0.05) [1]. Camicinal (GSK962040) induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg 1), driven by mean plasma concentrations >1.14 μmol L 1. After the effects of Camicinal (GSK962040) faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg 1 Camicinal (GSK962040) but at 6 mg kg 1, MMCs returned 253 min after dosing, compared with 101 min after saline (n = 5 each) [2]. he oral bioavailability (Fpo) of Camicinal (GSK962040) was found to be 48 ( 13%. Camicinal (GSK962040) shows a long lasting effect (T1/2 ) 46.9 ( 5.0 min at 3 μM) when compared with the short-lived effect of [Nle13]motilin (T1/2 ) 11.4 ( 1.5 min at 0.3 μM) [3]. Camicinal (GSK962040) strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only [4].

Reference

[1]. Sanger, G.J., et al., GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility. Neurogastroenterol Motil, 2009. 21(6): p. 657-64, e30-1.
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[2]. Leming, S., et al., GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs. Neurogastroenterol Motil, 2011. 23(10): p. 958-e410.
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[3]. Westaway, S.M., et al., Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-pi peridinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate. J Med Chem, 2009. 52(4): p. 1180-9.
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[4]. Broad, J., et al., Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists. Br J Pharmacol, 2012. 167(4): p. 763-74.
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