The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

The neuronal ceroid lipofuscinoses (NCLs) are a family of rare lysosomal storage disorders. The most common form of NCL occurs in children harboring a mutation in the CLN3 gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with current in vivo and in vitro models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier and establishes the suitability of an iPSC-derived neuron model of the disease to facilitate compound screening. Upon differentiation, hallmarks of CLN3 disease are apparent, including lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and attenuated Bcl-2 expression. The model led to the identification of small molecules that cleared subunit c accumulation by mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction.

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3Δex7/8 mice. WT/Cln3Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in Cln3Δex7/8 mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in Cln3Δex7/8 mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female Cln3Δex7/8 mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in Cln3Δex7/8 mice, paving the way for potential therapies for CLN3 disease.

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

<div> <div> <div> <p>The neuronal ceroid lipofuscinoses (NCLs) commonly referred to as Batten disease are a family of rare lysosomal storage disorders (LSDs). The most common form of NCL occurs in children harboring a mutation in the CLN3 gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with the current in vivo and in vitro models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier (BBB) and adds to the few available iPSC-derived neuron models of the disease. Upon differentiation, hallmarks of CLN3 disease were displayed including lipofuscin and subunit C of mitochondrial ATP synthase accumulation, mitochondrial dysfunction and aberrant lysosomal pH. Small molecules were identified that cleared subunit C accumulation by the mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction. </p> </div> </div> </div>

<div> <div> <div> <p>The neuronal ceroid lipofuscinoses (NCLs) commonly referred to as Batten disease are a family of rare lysosomal storage disorders (LSDs). The most common form of NCL occurs in children harboring a mutation in the CLN3 gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with the current in vivo and in vitro models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier (BBB) and adds to the few available iPSC-derived neuron models of the disease. Upon differentiation, hallmarks of CLN3 disease were displayed including lipofuscin and subunit C of mitochondrial ATP synthase accumulation, mitochondrial dysfunction and aberrant lysosomal pH. Small molecules were identified that cleared subunit C accumulation by the mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction. </p> </div> </div> </div>