Soft Drugs

and, Paul W. Erhardt; Reese, Michael D.

doi:10.1002/9783527633166.ch14

Cited by 6 publications

(1 citation statement)

References 51 publications

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“…Soft drugs are biologically active compounds that are designed to undergo metabolic inactivation by controlled conversion of the parent molecule into a predictable, nontoxic metabolite. , While soft drugs do not necessarily show fast inactivation, they can be optimized as locally acting compounds so that they retain sufficient stability in their target organ while being rapidly inactivated once entering systemic circulation. Such inactivation usually occurs in blood but can also be achieved in liver.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

et al. 2015

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ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However, systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

et al. 2015

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Prodrugs: Strategic Deployment, Metabolic Considerations, and Chemical Design Principles

Erhardt¹,

Khupse²,

Sarver³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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This article begins by providing a brief history about prodrugs, and then delineates their specific definition while contrasting them to “regular” drugs and to soft drugs. It continues by discussing their strategic deployment during today's drug discovery and development paradigm, including their union with biological molecules to produce antibody–drug conjugates (ADCs) which are becoming extremely popular as new molecular entities (NMEs). Metabolic considerations focus upon hydrolytic processes while emphasizing, in particular, the important roles that are often played by the carboxylesterases. Design aspects include both a listing of commonly deployed functional groups and a discussion of how to impact upon their reaction rates by manipulating steric features of the chemical constructs. While replete with chemical structures and metabolic reactions throughout, the next section highlights all prodrug entries within the NMEs entering the US marketplace for the periods 2004–2008 and 2009–2017. Cataloged information relevant to this section is provided in two comprehensive appendices. The article concludes by conveying three case studies, which further serve to highlight the practical applications of prodrug design principles.

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Esmolol (soft drug design)

Erhardt

2023

Overcoming Obstacles in Drug Discovery and Development

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Soft Drugs

Cited by 6 publications

References 51 publications

Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

Prodrugs: Strategic Deployment, Metabolic Considerations, and Chemical Design Principles

Esmolol (soft drug design)

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