Discovery of Novel 2-Anilinopyrazolo[1,5-a]pyrimidine Derivatives as c-Src Kinase Inhibitors for the Treatment of Acute Ischemic Stroke

Mukaiyama, Harunobu; Nishimura, Toshihiro; Shiohara, Hiroaki; Kobayashi, Satoko; Komatsu, Yoshimitsu; Kikuchi, Shinichi; Tsuji, Eiichi; Kamada, Noboru; Ohnota, Hideki; Kusama, Hiroshi

doi:10.1248/cpb.55.881

Cited by 29 publications

(11 citation statements)

References 21 publications

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“…Among the few studies reporting protective effects of PP1 or PP2 in ischemic stroke, although within a short 24-h period, only one study showed a comparable 6-h therapeutic window in a mouse pMCAO model (Paul et al, 2001). Preclinical efficacy profiles of SKI-606 and SKS-927 are also superior to those of other recently reported Src inhibitors (Mukaiyama et al, 2007), for which treatment was started 15 min poststroke, and no neurological recovery was evaluated, both findings with no clinical relevance. The predictive value of preclinical stroke models for a successful clinical trial has been poor even for agents that have shown efficacy when administered within several hours poststroke (O'Collins et al, 2006;Savitz and Fisher, 2007).…”

Section: Discussionmentioning

confidence: 94%

Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

Shi

Pong²,

Gonzales³

et al. 2009

J Pharmacol Exp Ther

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Src kinase signaling has been implicated in multiple mechanisms of ischemic injury, including vascular endothelial growth factor (VEGF)-mediated vascular permeability that leads to vasogenic edema, a major clinical complication in stroke and brain trauma.Here we report the effects of two novel Src kinase inhibitors, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile (SKI-606) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methypiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927), on ischemia-induced brain infarction and short-and longterm neurological deficits. Two well established transient [transient middle cerebral artery occlusion (tMCAO)] and permanent [permanent middle cerebral artery occlusion (pMCAO)] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario. Brain penetration of Src inhibitors, their effect on blood-brain barrier integrity and VEGF signaling in human endothelial cells were also evaluated. Our results demonstrate that both agents potently block VEGF-mediated signaling in human endothelial cells, penetrate rat brain upon systemic administration, and inhibit postischemic Src activation and vascular leakage. Treatment with SKI-606 or SKS-927 (at the doses of 3-30 mg/kg i.v.) resulted in a dose-dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4-to 6-h after tMCAO. Src blockade after pMCAO resulted in accelerated improvement in recovery from motor, sensory, and reflex deficits during a long-term (3 weeks) testing period poststroke. These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke.Ischemic stroke is a life-threatening disorder, with no effective therapy except for intravascular thrombolysis with recombinant tissue plasminogen activator or, in some instances, surgical removal of the obstructing blood clot with interventional devices (Donnan et al., 2008;Zaleska et al., 2009). However, the risk of hemorrhage and a restrictive 3-to 4.5-h treatment window (Hacke et al., 2008) reduce the pool of patients eligible for treatment with recombinant tissue plasminogen activator to only 5 to 8%. Despite continued improvement in our understanding of mechanisms underlying ischemic damage and the identification of numerous neuroprotective agents effective in animal models, no agent has yet demonstrated significant benefit in the clinic (O'Collins et al., 2006;Savitz and Fisher, 2007;Zaleska et al., 2009). Hence, the development of stroke therapeutic agents remains a daunting challenge as does the urgent need for new agents.The Src family of nonreceptor protein tyrosine kinases (PTKs) coordinate a broad spectrum of physiological responses including extracellular signals derived from growth facto...

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Section: Discussionmentioning

confidence: 94%

Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

Shi

Pong²,

Gonzales³

et al. 2009

J Pharmacol Exp Ther

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“…Reaction of 18a with the desired β-ketoester 19a−h in a mixture of acetic acid/water at 120°C gave the final products in reasonable yields (16−70%), with most products collected by filtration on cooling. 40 The β-ketoester 19h was prepared following procedures described by Brooks et al (Scheme 2). 41 The carboxylic acid 20 was converted to the activated imidazolide using CDI and was then treated without isolation with the magnesium salt of malonic acid to give 19h.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The methanol fraction was evaporated under reduced pressure to give the title product 38 as a white solid (349 mg, 85%, 92% area by LC−MS). 1 3-(4-Chlorophenyl)-1-morpholinopropane-1-thione (40). A mixture of 1-(4-chlorophenyl)propan-1-one 39 (2 g, 12 mmol), morpholine (4 mL, 46 mmol), and sulfur (0.77 g, 23.9 mmol) was heated at 130°C for 24 h under nitrogen with a bleach scrubber.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

et al. 2015

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The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.

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“…Pronounced biological activity of pyrazolo-[1,5-a]pyrimidine derivatives was noted in [10][11][12][13][14][15][16][17].…”

mentioning

confidence: 99%

“…Several efficient medical agents exhibiting sedative and soporific activity (such as Zaleplon [2], Indiplon [3], and Ocinaplon [4]) are known; some compounds of this series have been patented as antidiabetic [5] and antiphlogistic agents [6], antidepressants [7], and analgesics [8,9]. Pronounced biological activity of pyrazolo- [1,5-a]pyrimidine derivatives was noted in [10][11][12][13][14][15][16][17].…”

mentioning

confidence: 99%

α-Amino azoles in the synthesis of heterocycles: VI. Synthesis and structure of cycloalkane-annulated pyrazolo[1,5-a]pyrimidines

et al. 2009

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Reactions of 4-aryl-1H-pyrazol-5(3)-amines with 2-acylcycloakanones and 2-acyl-5,5-dimethylcyclohexane-1,3-diones led to the formation of regioisomeric 6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline, 5,6,7,8-tetrahydropyrazolo[5,1-b]quinazoline, and 7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine derivatives. The product structure was determined by X-ray analysis and 1 H and 13 C NMR spectroscopy. * For communication V, see [1]. Extensive development of synthetic approaches to polyfunctional pyrazolo[1,5-a]pyrimidine derivatives is stimulated by the fact that compounds possessing pyrazole and pyrimidine fragments are promising as potential biologically active substances. Several efficient medical agents exhibiting sedative and soporific activity (such as Zaleplon [2], Indiplon [3], and Ocinaplon [4]) are known; some compounds of this series have been patented as antidiabetic [5] and antiphlogistic agents [6], antidepressants [7], and analgesics [8,9]. Pronounced biological activity of pyrazolo-[1,5-a]pyrimidine derivatives was noted in [10][11][12][13][14][15][16][17].The goal of the present work was to study regioselectivity in the formation of cycloalkane-annulated pyrazolo[1,5-a]pyrimidines and determine characteristic 13 C NMR spectral parameters of particular regioisomers. We examined reactions of 5(3)-amino-4-aryl-1H-pyrazoles Ia-Id with 2-acylcycloalkanones III-VII and three-component condensation of 5(3)-amino-4-aryl-1H-pyrazoles Ia and Id with dimedone and aldehydes.Aminopyrazoles I reacted with 2-ethoxymethylidene-5,5-dimethylcyclohexane-1,3-dione (II) and 2-acetyl-5,5-dimethylcyclohexane-1,3-dione (III) to give only substituted 6,7,8,9-tetrahydropyrazolo-[1,5-a]quinazolines which may be regarded as pyrazolopyrimidines fused at the C 6 -C 7 bond to cyclohexene ring. The reaction begins with nucleophilic attack by the amino nitrogen atom of pyrazole I at the carbon atom of the ethoxymethylidene or acetyl group in II or III, respectively. In the first case, the primary linear adduct, 5,5-dimethyl-2-{[(3-methyl-4-phenyl-1H-pyrazol-5-yl)amino]methylidene}cyclohexane-1,3-dione (A), was isolated as individual substance, while in the second case, 3-hydroxy-5,5-dimethyl-2-{1-[(4-phenyl-1H-pyrazol-3-yl)imino]ethyl}cyclohex-2-en-1-one (B) was detected as intermediate product by 1 H NMR (Scheme 1). The formation of an analogous intermediate compound was observed previously in the reaction of 5-methoxymethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione with 5(3)-aminopyrazoles [18]. In the 1 H NMR spectrum of compound A, the NH proton in the pyrazole ring resonated at δ 12.82 ppm, and the exocyclic CH= and NH protons gave doublets at δ 8.65 and 12.76 ppm, respectively, with a coupling constant 3 J of 13.1 Hz. The downfield position of the latter NH signal indicates formation of intramolecular hydrogen bond NH · · · O. The structure of intermediate B was determined by 1 H NMR monitoring of the reaction of aminopyrazole Id with acetyldimedone III in DMSO-d 6 at 20°C. After 2 days, the 1 H NMR spectrum of the reaction...

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Discovery of Novel 2-Anilinopyrazolo[1,5-a]pyrimidine Derivatives as c-Src Kinase Inhibitors for the Treatment of Acute Ischemic Stroke

Cited by 29 publications

References 21 publications

Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

Neuroprotective Profile of Novel Src Kinase Inhibitors in Rodent Models of Cerebral Ischemia

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

α-Amino azoles in the synthesis of heterocycles: VI. Synthesis and structure of cycloalkane-annulated pyrazolo[1,5-a]pyrimidines

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