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Synthesis, Structure Activity Relationships and Preclinical evaluation of Heteroaromatic Amides and 1,3,4Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists Ramakrishna Nirogi, Abdul Rasheed Mohammed, Anil K. Shinde, Shankar Reddy Gagginapally, Durga Malleshwari Kancharla, Vanaja Reddy Middekadi, Narsimha Bogaraju, Srinivasa Rao Ravella, Pooja Singh, Sumit Raosaheb Birangal, Ramkumar Subramanian, Raghava Choudary Palacharla, Vijay Benade, Nageswararao Muddana, and Pradeep Jayarajan J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b00457 • Publication Date (Web): 15 May 2018 Downloaded from http://pubs.acs.org on May 15, 2018
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Journal of Medicinal Chemistry
Synthesis, Structure Activity Relationships and Preclinical evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists Ramakrishna Nirogi,* Abdul Rasheed Mohammed, Anil K. Shinde, Shankar Reddy Gagginapally, Durga Malleshwari Kancharla, Vanaja Reddy Middekadi, Narsimha Bogaraju, Srinivasa Rao Ravella, Pooja Singh, Sumit Raosaheb Birangal, Ramkumar Subramanian, Raghava Choudary Palacharla, Vijay Benade, Nageswararao Muddana, Pradeep Jayarajan. Suven Life Sciences Limited, Discovery Research, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad - 500 034, India KEYWORDS. 5-HT4 receptor, Structure Activity Relationships, Pharmacokinetic profile, Receptor occupancy, Cognitive deficits, Alzheimer’s disease, GR-125487 ABSTRACT. Alzheimer's disease (AD) is a neurodegenerative disorder which has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. The 5-HT4 receptor (5HT4R) partial agonists offer both symptomatic and disease modifying treatment as they shift amyloid precursor protein (APP) processing from amyloidogenic to non-amyloidogenic pathway
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by activating α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing neurotransmitter acetylcholine levels in the brain. Fascinated by dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophore were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon focused structure activity relationships, compound 4o was identified as potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5HT4R antagonist attenuated the activity of compound 4o in cognition model NORT. INTRODUCTION AD is a progressively debilitating neurodegenerative disorder, affecting mostly the aging population. Although the underlying causative factors are yet to be identified, symptoms include confusion, memory loss, and dementia, ultimately leading to death. The current pharmacotherapy provides only symptomatic relief through augmentation of cholinergic function with undesired side effects such as nausea, vomiting and bradycardia. Moreover, no disease modifying therapy is available to the patients till date. Thus, there is a need of new therapeutic targets for the treatment of this disorder and 5-HT4R is one such receptor which has attracted lot of attention. The 5-HT4R belongs to the superfamily of seven trans-membrane G-protein coupled receptors (GPCRs) and is coupled to G protein containing Gαs subunit.1 The 5-HT4R is reported to have potential role in many central nervous system (CNS) such as AD2 and peripherally mediated disorders such as irritable bowel syndrome2 and gastroparesis.4 The 5-HT4 receptors are highly expressed in brain regions like hippocampus, amygdala and cerebral cortex suggesting the involvement of receptor in cognitive processes.5 The 5-HT4R agonists modulate amyloid precursor protein (APP) derived peptides, amyloid beta (Aβ) and soluble amyloid precursor protein alpha (sAPPα).6
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Journal of Medicinal Chemistry
The sAPPα is non-amyloidogenic protein and it is reported to have potent neuroprotective role against neurotoxic effects of glutamate and β-amyloid.6 Human 5-HT4R isoforms are positively coupled to adenylyl cyclase production. Thus, activation of this G-protein coupled receptor activates adenylyl cyclase consequently increasing the production of cAMP. The increased cAMP in turn increases sAPPα release. The stimulatory effect of 5-HT4R receptor on sAPPα release is mimicked by forskolin, a direct activator of adenylyl cyclase, and 8-bromo-cAMP (membrane permeant cAMP analogue) suggesting the involvement of adenylyl cyclase and cAMP in modulating sAPPα by 5-HT4R.7 The 5-HT4R also increases the neuronal acetylcholine (ACh) levels in the brain.8 Thus, 5-HT4R partial agonists may be of use for both diseasemodifying and symptomatic treatment of cognitive disorders. The 5-HT4R owing to its dual mechanism of action to treat AD and other cognition related diseases became an attractive target for drug discovery. Several structurally diverse heteroaromatic derivatives9-13 as 5-HT4R agonists/partial agonists have been explored for both CNS and peripheral indications. The 5HT4R partial agonist PRX-03140 showed significant improvement of ADAS-cog score in Phase2a study for AD.14,15 Apart from this compound, several other compounds were in development such as BIMU-1,16 RS-67333,17 prucalopride3 and PF-049952749 among others (Figure 1). In our continuous efforts in discovering novel small molecules to treat AD with diverse mechanism of actions,18-20 we shifted our attention on 5-HT4R agonists partly due to their dual mechanism of action and partly due to availability of proof of concept in the form of PRX-03140 phase-2 positive results. Our internally discovered clinical candidate SUVN-D4010, a 5-HT4R partial agonist has completed Phase-1 clinical trials in healthy subjects21 and also completed Phase-2 enabling long term safety studies. The structure of this compound has not been disclosed so far.
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Most of the reported 5-HT4R ligands, which have been explored for both CNS and peripheral indications belong to either benzamide or imidazole carboxamide scaffold. Previous work19 from our group disclosed a series of 3-isopropylimidazo[1,5-a]pyridine carboxamide derivatives (5a, Series-1) as 5-HT4R partial agonists which displayed cognition enhancing properties in animal models. However, the brain penetration of these compounds was poor (Cbrain/Cplasma =
