- Email: [email protected]
RATIONAL-BASED DESIGN AND DEVELOPMENT OF QUINAZOLINE-BASED SMALL-MOLECULES: MULTI-TARGETING POTENTIAL FOR ALZHEIMERIC PATHOLOGIES
P438
Poster Presentations: Sunday, July 24, 2016
Background: Recruitment methods have demonstrated to influence sample characteristics in Alzheimer Disease (AD) studies [1-5], and there is insufficient information regarding its impact in SCD; therefore our aim is to compare sample characteristics in SCD subjects recruited from two settings: memory unit (MU) vs Open House Initiative (OHI), an activity conducted at Fundacio ACE, where it is offered free cognitive screening to Barcelona citizens. Methods: Subjects evaluated at Fundacio ACE between January 2013 and August 2015, who fulfill SCD proposed criteria [6] were selected. It was compared data regarding: age, gender, level of education, familiar history of dementia, personal history of depression, MMSE scores, comprehensive neuropsychological examination, frequency of APOE E4 and amyloid burden measured with (18)F-florbetaben (FBB) PET imaging (when available). A linear regression analysis (LRA), using gender and years of education as covariates were used to examine the neuropsychological variables. Results: 326 subjects were selected: 220 OHI and 106 MU. In comparison with MU sample, OHI were mostly women (75.9%% vs 64.5%], p<0.05), with higher education level (12.15 [3.71] vs 10.70 years [3.80], p¼0.001) and more familiar history of dementia (138 [62.7%] vs 44 [41.5%], p<0.001); without statistical significant differences in age or depression history. OHI sample showed better performance in MMSE and neuropsychological tests, except for constructive praxis, verbal long term memory and visual recognition; and after LRA, this this trend continued in automatic response inhibition capacity, abstract reasoning and memory recognition (Table 1). We did not find differences between samples in APOE E4 carriers (one or two alleles) (MU 25.4% vs OHI 24%, p¼0.821) or in amyloid burden measured with FBB in 66 subjects (SUVR MU 1.24 vs SUVR OHI 1.18, p¼0.551). There were not correlations with the neuropsychological performance and the presence of one or two APOE E4 alleles or the amyloid burden. Conclusions: Subjects with SCD from two samples showed different demographic and neuropsychological characteristics, without significance difference in APOE E4 carriers or in the amyloid burden; and these differences should be considered in the design of SCD’s research, to avoid the selection bias that can influence the results and conclusions of these studies.
P1-097
RATIONAL-BASED DESIGN AND DEVELOPMENT OF QUINAZOLINE-BASED SMALL-MOLECULES: MULTI-TARGETING POTENTIAL FOR ALZHEIMERIC PATHOLOGIES
Tarek Mohamed, Praveen P. Nekkar Rao, University of Waterloo, Waterloo, ON, Canada. Contact e-mail: [email protected]
Background: A key target of AD pathology is that tied with the misfolding and aggregating mechanisms of amyloidogenic proteins (abeta and tau). Although both species have essential roles in normal physiology and development, in AD, they are heavily implicated in the rapid formation of neurotoxic aggregates (plaques and neurofibrillary tangles) that destroy neuronal tissue and give rise to cognitive impairment. In addition to these neurotoxic species, the cholinesterases (AChE and BuChE) have long been the go-to targets for maintaining the levels of acetylcholine (ACh) in the brain. By maintaining the levels of that critical neurotransmitter (ACh), neurons are able to carry with communication pathways in the brain and therefore, reducing cognitive impairment. Methods: Utilizing CADD (Computer-aided drug design), a library of w 100 quinazoline-based derviatives were developed and screened for dual AChE/BuChE inhibition and abeta aggregation (Ab-40/42) inhibition. We also assessed the aggregation kinetics of Ab with and without lead candidates to determine potential modes of inhibtiion. Transmission electron microscopy (TEM) was also utilized to assess Ab morpholgy. Lead candidates are in the process of evaluation for anti-oxidant and metal chelation potential as well as screening against tau aggregation. Results: A large majority of these quinazoline-based derivatives were active toward both ChE enzymes and have displayed a wide range of inhibitory activity toward Ab-40/42 aggregation. We also observed multi-mode inhibition of Ab-40/42 aggregation based on our kinetic ThT-monitoring assays. Conclusions: The accumulating SAR (structure-activity relationship) data strongly suggests the suitability of utilizing the versatile quinazoline ring scaffold to design, develop and evaluate a widerange of multi-target candidates capable of eliciting disease-modifying effects.
Table 1 Comparison of neuropsychological performance in subjects with SCD between samples Cognitive functions
OHI
MU
p value
Cohen’s d
Language Praxis
14.89 (0.34) 3.93 (0,28) 3.98 (0,13) 20.86 (5.13) 17.46 (4.23) 21.74 (4.85) 13.63 (1.50) 31.04 (5.36) 23.14 (1.04) 4.35 (0.90) 7.76 (1.86) 3.84 (0.36) 8.57 (2.04) 9.97 (0.20)
14.74 (0.50) 3.88 (0.41) 3.91 (0.33) 24.92 (5.96) 15.11 (4.16) 19.00 (4.39) 12.38 (1.94) 28.79 (5.29) 22.58 (1.47) 4.10 (0.86) 7.41 (2.09) 3.66 (0.51) 8.19 (1.77) 9.92 (0.27)
0.002 0.199 0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.022 0.135 <0.001 0.028 0.097
0.380 0.152 0.357 -0.749 0.560 0.582 0.754 0.416 0.474 0.272 0.178 0.439 0.261 0.197
Visual confrontation naming Mean /SD Constructive Mean /SD Ideomotor Mean /SD Executive function Automatic response inhibition capacity Mean /SD Phonetic verbal fluency Mean /SD Semantic verbal fluency Mean /SD Abstract reasoning Mean /SD Memory Learning capacity Mean /SD Recognition memory Mean /SD Working memory Mean /SD Verbal long term memory Mean/SD Visuospatial function Mean /SD Attention Mean /SD Visual recognition Mean /SD
Poster Presentations: Sunday, July 24, 2016
Background: Recruitment methods have demonstrated to influence sample characteristics in Alzheimer Disease (AD) studies [1-5], and there is insufficient information regarding its impact in SCD; therefore our aim is to compare sample characteristics in SCD subjects recruited from two settings: memory unit (MU) vs Open House Initiative (OHI), an activity conducted at Fundacio ACE, where it is offered free cognitive screening to Barcelona citizens. Methods: Subjects evaluated at Fundacio ACE between January 2013 and August 2015, who fulfill SCD proposed criteria [6] were selected. It was compared data regarding: age, gender, level of education, familiar history of dementia, personal history of depression, MMSE scores, comprehensive neuropsychological examination, frequency of APOE E4 and amyloid burden measured with (18)F-florbetaben (FBB) PET imaging (when available). A linear regression analysis (LRA), using gender and years of education as covariates were used to examine the neuropsychological variables. Results: 326 subjects were selected: 220 OHI and 106 MU. In comparison with MU sample, OHI were mostly women (75.9%% vs 64.5%], p<0.05), with higher education level (12.15 [3.71] vs 10.70 years [3.80], p¼0.001) and more familiar history of dementia (138 [62.7%] vs 44 [41.5%], p<0.001); without statistical significant differences in age or depression history. OHI sample showed better performance in MMSE and neuropsychological tests, except for constructive praxis, verbal long term memory and visual recognition; and after LRA, this this trend continued in automatic response inhibition capacity, abstract reasoning and memory recognition (Table 1). We did not find differences between samples in APOE E4 carriers (one or two alleles) (MU 25.4% vs OHI 24%, p¼0.821) or in amyloid burden measured with FBB in 66 subjects (SUVR MU 1.24 vs SUVR OHI 1.18, p¼0.551). There were not correlations with the neuropsychological performance and the presence of one or two APOE E4 alleles or the amyloid burden. Conclusions: Subjects with SCD from two samples showed different demographic and neuropsychological characteristics, without significance difference in APOE E4 carriers or in the amyloid burden; and these differences should be considered in the design of SCD’s research, to avoid the selection bias that can influence the results and conclusions of these studies.
P1-097
RATIONAL-BASED DESIGN AND DEVELOPMENT OF QUINAZOLINE-BASED SMALL-MOLECULES: MULTI-TARGETING POTENTIAL FOR ALZHEIMERIC PATHOLOGIES
Tarek Mohamed, Praveen P. Nekkar Rao, University of Waterloo, Waterloo, ON, Canada. Contact e-mail: [email protected]
Background: A key target of AD pathology is that tied with the misfolding and aggregating mechanisms of amyloidogenic proteins (abeta and tau). Although both species have essential roles in normal physiology and development, in AD, they are heavily implicated in the rapid formation of neurotoxic aggregates (plaques and neurofibrillary tangles) that destroy neuronal tissue and give rise to cognitive impairment. In addition to these neurotoxic species, the cholinesterases (AChE and BuChE) have long been the go-to targets for maintaining the levels of acetylcholine (ACh) in the brain. By maintaining the levels of that critical neurotransmitter (ACh), neurons are able to carry with communication pathways in the brain and therefore, reducing cognitive impairment. Methods: Utilizing CADD (Computer-aided drug design), a library of w 100 quinazoline-based derviatives were developed and screened for dual AChE/BuChE inhibition and abeta aggregation (Ab-40/42) inhibition. We also assessed the aggregation kinetics of Ab with and without lead candidates to determine potential modes of inhibtiion. Transmission electron microscopy (TEM) was also utilized to assess Ab morpholgy. Lead candidates are in the process of evaluation for anti-oxidant and metal chelation potential as well as screening against tau aggregation. Results: A large majority of these quinazoline-based derivatives were active toward both ChE enzymes and have displayed a wide range of inhibitory activity toward Ab-40/42 aggregation. We also observed multi-mode inhibition of Ab-40/42 aggregation based on our kinetic ThT-monitoring assays. Conclusions: The accumulating SAR (structure-activity relationship) data strongly suggests the suitability of utilizing the versatile quinazoline ring scaffold to design, develop and evaluate a widerange of multi-target candidates capable of eliciting disease-modifying effects.
Table 1 Comparison of neuropsychological performance in subjects with SCD between samples Cognitive functions
OHI
MU
p value
Cohen’s d
Language Praxis
14.89 (0.34) 3.93 (0,28) 3.98 (0,13) 20.86 (5.13) 17.46 (4.23) 21.74 (4.85) 13.63 (1.50) 31.04 (5.36) 23.14 (1.04) 4.35 (0.90) 7.76 (1.86) 3.84 (0.36) 8.57 (2.04) 9.97 (0.20)
14.74 (0.50) 3.88 (0.41) 3.91 (0.33) 24.92 (5.96) 15.11 (4.16) 19.00 (4.39) 12.38 (1.94) 28.79 (5.29) 22.58 (1.47) 4.10 (0.86) 7.41 (2.09) 3.66 (0.51) 8.19 (1.77) 9.92 (0.27)
0.002 0.199 0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.022 0.135 <0.001 0.028 0.097
0.380 0.152 0.357 -0.749 0.560 0.582 0.754 0.416 0.474 0.272 0.178 0.439 0.261 0.197
Visual confrontation naming Mean /SD Constructive Mean /SD Ideomotor Mean /SD Executive function Automatic response inhibition capacity Mean /SD Phonetic verbal fluency Mean /SD Semantic verbal fluency Mean /SD Abstract reasoning Mean /SD Memory Learning capacity Mean /SD Recognition memory Mean /SD Working memory Mean /SD Verbal long term memory Mean/SD Visuospatial function Mean /SD Attention Mean /SD Visual recognition Mean /SD