N-Nitrosamines as Cancerogenic Impurities

Since 2018, several drugs have been recalled from the market following the discovery of N-nitrosamine impurities in their commercial batches. The N-nitrosamines have been linked to an elevated risk of several cancers especially in case of continuous intake. Since 2020, the FDA and other authorities worldwide have mandated control of N-nitrosamine levels in commercial drugs.

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Mechanism

N-nitrosamines can form as impurities in the process of chemical drug production. Following the drug administration, oxidation of the N-nitrosamine species by cytochrome P450 leads to downstream production of cancerogenic diazonium salts that damage DNA by alkylation of susceptible nucleobases. Acceptable daily intake limits have been mandated by authorities for a large panel of N-nitrosamine species, which is, however, not explicit.

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More than 200 N-nitrosamines from stock on a 5-10 g scale.

Saturated bioisosteres of meta-substituted benzene

Saturated bioisosteres of meta-substituted benzene offer several advantages in drug design and medicinal chemistry. They can enhance the metabolic stability of a molecule, improving its bioavailability. These bioisosteres also allow for the modulation of a molecule's lipophilicity, optimizing its solubility and permeability properties. Additionally, they can alter the interaction of a molecule with its target receptor, improving potency and specificity. The use of bioisosteres can provide opportunities for intellectual property protection by creating novel chemical entities. Enamine offers a variety of saturated bioisosteres of meta-substituted benzene.

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Design

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More than 100 bioisosteres from stock on a 5-10 g scale.

EN300-7640676

EN300-1472308

EN300-27188232

EN300-385269

EN300-7542933

EN300-21646228

EN300-90662

EN300-380986

EN300-1724197

EN300-6764720

EN300-396745

EN300-6733197

EN300-6474965

EN300-6491479

EN300-301433

EN300-37152409

EN300-12449149

EN300-87438

EN300-33047966

EN300-28262753

EN300-6475858

EN300-88109

EN300-331599

EN300-39854956

EN300-24776816

EN300-61211

EN300-45271945

EN300-45561636

EN300-27781042

EN300-44829058

EN300-45489679

EN300-1703908

EN300-7434894

EN300-26676840

EN300-7460561

EN300-88150

EN300-7424901

EN300-37330647

EN300-37330564

EN300-27118152

EN300-37330984

EN300-7037933

Fluorinated Benzodioxoles

Drugs with the benzodioxole moiety showed excellent bioavailability and low cytotoxicity. The benzodioxole structure inspired the creation of fluorinated analogues to improve drug-target interactions and metabolic stability. Lumacaftor and Tezacaftor represent an innovative type of drugs: the small molecule chaperones. The difluoro-1,3-benzodioxol-5-yl-cyclopropane carboxamide group, shared between both drugs, binds to the nascent chain of the mutant protein during its biosynthesis. In this way, the protein corrects the folding defects and escapes premature degradation that could cause disease. Enamine offers a variety of advanced building blocks that share the fluorinated benzodioxole core structure.

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Concept

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More than 100 fluorinated benzodioxoles and analogues from stock on a 5-10 g scale.

Bioisosteres of tert-butyl group

The tert-butyl group (-C(CH₃)₃) is a common motif in drug design due to its steric and electronic properties. Its bulky size and non-polar nature can be mimicked by other groups. Examples of bioisosteres of the tert-butyl group include cyclopropyl, cyclobutyl, isopropyl, and fluorine. These compounds can be used to modify the lipophilicity, solubility, and pharmacokinetic properties of a drug molecule to improve its efficacy and safety.

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Concept

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More than 100 bioisosteres of tert-butyl group from stock on a 5-10 g scale.

EN300-105951

EN300-201143

EN300-64916

EN300-190797

EN300-82379

EN300-7072438

EN300-1086652

EN300-1971139

EN300-36596799

EN300-184706

EN300-267428

EN300-26621242

EN300-6234030

EN300-37339061

EN300-5393231

EN300-1152860

EN300-94391

EN300-210303

EN300-88141

EN300-1973471

EN300-104181

EN300-206421

EN300-26667284

EN300-35964645

EN300-141346

EN300-1223580

EN300-156604

EN300-1178233

EN300-1706136

EN300-1822067

EN300-27108223

EN300-6492294

EN300-182098

EN300-202546

EN300-126441

EN300-189050

EN300-135958

EN300-247368

EN300-7032852

EN300-1930746

Non-traditional fluoroalkyl groups

A wide variety of fluoroaliphatic moieties remain severely underexplored in drug design, in contrast to the CF₃-group, which is among the most frequently found fragments in modern pharmaceuticals. In recent years, a growing set of examples have demonstrated a considerable potential of variable non-traditional fluoroalkyl groups in both, medicinal chemistry and agrochemical fields. These structures may address the issues associated with lipophilicity profile and metabolic degradation schemes of biologically active molecules.

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Concept

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More than 100 non-traditional fluoroaliphatic compounds from stock on a 5-10 g scale.