Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients. In ...nonclinical assessments, 1 was mainly eliminated by CYP3A4-mediated metabolism, therefore at the risk of being a victim of drug–drug interactions (DDI) with CYP3A4 inhibitors and inducers. An effort was initiated to identify a new D1 PAM with an improved DDI risk profile. While attempts to introduce additional metabolic pathways mediated by other CYP isoforms failed to provide molecules with an acceptable profile, we discovered that the relative contribution of CYP-mediated oxidation and UGT-mediated conjugation could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have identified LY3154885 (5), a D1 PAM that possesses similar in vitro and in vivo pharmacologic properties as 1, but is metabolized mainly by UGT, predicting it could potentially offer lower victim DDI risk in clinic.
Structure–activity relationship analysis identified (+)-N-(3-aminopropyl)-N-1-(5-benzyl-3-methyl-4-oxo-1,2thiazolo5,4-dpyrimidin-6-yl)-2-methylpropyl-4-methylbenzamide (AZD4877), from a series of ...novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between ...decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
The synthesis and structure–activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists ...were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
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-methyldecahydro-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.
The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable ...metabolic stability and exhibiting minimal drug–drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
Stroke Center Readiness in the PACU Filla, Sandra; Davis, Gail
Journal of perianesthesia nursing,
August 2015, 2015-08-00, Letnik:
30, Številka:
4
Journal Article
Compound 1a (LY334370), a selective 5-HT1F receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy ...for the acute treatment of migraine. Although 1a was greater than 100-fold selective over both the 5-HT1B and 5-HT1D receptors, it exhibited appreciable 5-HT1A receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo2,3-cpyridine and pyrrolo3,2-bpyridine (2a and 3a) as well as pyrrolo3,2-dpyrimidine (4a) analogues of 1a, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5-HT1 receptor subtypes. The pyrrolo3,2-bpyridine analogue 3a showed high 5-HT1F receptor affinity but offered no improvement in selectivity compared to 1a. However, the C-5 acetamide derivative, 3b, was greater than 100-fold selective over the 5-HT1A, 5-HT1B, and 5-HT1D receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5-HT1F receptor. Replacement at C-5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.
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