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Nervous System Diseases

Small molecule drug

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Disease Domain	Count

Nervous System Diseases	1

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Small molecule drug	1

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GluK5 x Kainate receptor	1

Author: Lee A. Phebus ; Marlene Cohen ; Ken H. Ho ; Brianne Weiss ; Kirk W. Johnson ; Mary Katofiasc ; Bryan Johnson ; Edward L. Mattiuz ; Ann Marie Ogden ; David O. Calligaro ; Paul L. Ornstein ; Donna K. Dieckman ; Amy Clemens-Smith ; Robert E. Stratford ; Sandra A. Filla ; Rebecca A. Wright ; David Bleakman ; Darryle Schoepp ; Geihan Rizkalla ; Keith Jarvie ; Andrew Alt ; Mary Gates ; Kathryn Schenck ; Craig Salhoff

The excitatory neurotransmitter glutamate has been implicated in both migraine and persistent pain. The identification of the kainate receptor GLU(K5) in dorsal root ganglia, the dorsal horn, and trigeminal ganglia makes it a target of interest for these indications. We examined the in vitro and in vivo pharmacology of the competitive GLU(K5)-selective kainate receptor antagonist LY466195 [(3S,4aR,6S,8aR)-6-[[(2S)-2-carboxy-4,4-difluoro-1-pyrrolidinyl]-methyl]decahydro-3-isoquinolinecarboxylic acid)], the most potent GLU(K5) antagonist described to date. Comparisons were made to the competitive GLU(K5)/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid], other decahydroisoquinoline GLU(K5) receptor antagonists, and the noncompetitive AMPA receptor antagonist LY300168 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi-azepine]. When characterized electrophysiologically in rat dorsal root ganglion neurons, LY466195 antagonized kainate (30 microM)-induced currents with an IC50 value of 0.045 +/- 0.011 microM. In HEK293 cells transfected with GLU(K5), GLU(K2)/GLU(K5), or GLU(K5)/GLU(K6) receptors, LY466195 produced IC50 values of 0.08 +/- 0.02, 0.34 +/- 0.17, and 0.07 +/- 0.02 microM, respectively. LY466195 was efficacious in a dural plasma protein extravasation (PPE) model of migraine with an ID100 value of 100 microg/kg i.v. LY466195 was also efficacious in the c-fos migraine model, with a dose of 1 microg/kg i.v. significantly reducing the number of Fos-positive cells in the rat nucleus caudalis after electrical stimulation of the trigeminal ganglion. Furthermore, LY466195 showed no contractile activity in the rabbit saphenous vein in vitro. The diethyl ester prodrug of LY466195 was also efficacious in the same PPE and c-fos models after oral administration at doses of 10 and 100 microg/kg, respectively while having no N-methyl-D-aspartate antagonist-like behavioral effects at oral doses up to 100 mg/kg.

01 Feb 2001·IDrugs : the investigational drugs journal

Recent advances in 5-HT(1D)-selective agonists.

Article

Author: Isaac, M ; Slassi, A

01 Aug 2000·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

5-Alkyltryptamine derivatives as highly selective and potent 5-HT1D receptor agonists

Q4 · MEDICINE

Article

Author: Hynd, D. ; Rakhit, S. ; Meng, C. Q. ; Edwards, L. ; MacLean, N. ; Chen, C. ; Xin, T. ; Wang, H. ; Seto, C. ; O'Brien, A. ; Lee, D. K. H. ; Kamboj, R. ; Slassi, A.

A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine.

100 Deals associated with NPS Allelix Corp.

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100 Translational Medicine associated with NPS Allelix Corp.

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Pipeline

Pipeline Snapshot as of 25 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

LY-466195 ( GluK5 x Kainate receptor )	Migraine Disorders More	Preclinical
ALX-0388 ( 5-HT1B receptor )	Migraine Disorders More	Discontinued
Interleukin-6(NPS Allelix Corp.) ( IL-6R )	Inflammation More	Discontinued
ALX-0625	Migraine Disorders More	Discontinued
ALX-0646 ( 5-HT1D receptor )	Migraine Disorders More	Discontinued