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The cyclopentane carbocyclic ring system, while ubiquitous in nature, is not usually considered a privileged core structure for the development of a drug candidate due, in part, to a perceived synthetic intractability of stereochemically complex target molecules. In this review, we demonstrate that the cyclopentane motif has been utilized as an effective core scaffold for several highly successful medicinal chemistry programs and, thus, has provided an underappreciated yet significant value for biomedical research. Moreover, the modern synthetic methods highlighted in this work offer a wealth of attractive and accessible technologies for the stereocontrolled construction of exceedingly complex cyclopentanoid chemotypes of natural and unnatural origin. We contend that the cyclopentane framework should be regarded as a privileged scaffold for drug discovery research and that expanded screening campaigns of novel cyclopentane- based small molecule libraries for therapeutically relevant biological properties will have a favorable impact on the development of the active pharmaceutical ingredients (APIs) of tomorrow. © 2014 Bentham Science Publishers.


Heasley B.,SCYNEXIS
Angewandte Chemie - International Edition | Year: 2011

Reactive response: Tetracyclines are potent antimicrobial agents-however, their high consumption level has contributed to the emergence of widespread bacterial resistance, which in turn stimulates the systematic search for new tetracycline analogues. In recent years, new synthetic methods have emerged that provide access to a broad range of tetracycline analogues. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Heasley B.,SCYNEXIS
Chemistry - A European Journal | Year: 2012

The active components from the extracts of Digitalis, cardiotonic steroid glycosides, have been ingested by humans for more than 200 years as a medicinal therapy for heart failure and abnormal heart rhythms. The positive inotropic activity of the cardiotonic steroids that mediates clinically useful physiological effects in patients has been attributed largely to a high affinity inhibitory interaction with the extracellular surface of the membrane-bound sodium pump (Na +/K +-ATPase). However, previously unrecognized intracellular signaling pathways continue to be uncovered. This Review examines both partial and de novo synthetic approaches to the medicinally important and structurally captivating cardenolide and bufadienolide steroid families, with an emphasis on the stereocontrolled construction of the pharmacophoric aglycone (genin) framework. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Jacobs R.T.,SCYNEXIS
Future medicinal chemistry | Year: 2011

Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity and the complexity of treatment regimens. We have discovered and optimized a series of benzoxaborole-6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.


This invention relates to cyclosporin derivatives of general formula (I): wherein A, B, R^(1), R^(2 )and X are as defined in the specification, and pharmaceutical compositions prepared from the same, for use in treatment of hepatitis C virus.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 223.99K | Year: 2015

DESCRIPTION provided by applicant Due to poor outcomes of patients with invasive fungal infections and expensive health care needs of these patients invasive fungal infections carry exceedingly high human and financial costs The cost of invasive fungal infections to the healthcare system is conservatively estimated to be $ billion annually in the US alone Current antifungal agents can have limited clinical efficacy are occasionally toxic and are increasingly ineffective due to emerging resistance Despite this need no completely novel class of antifungals has been developed in over years This project seeks to address the need for new therapies by targeting a signal transduction network required for invasive fungi to survive in humans Calcineurin is a highly conserved protein phosphatase that is important in mediating cell stress responses and necessary for invasive fungal disease Currently available calcineurin inhibitors cyclosporine A CsA and tacrolimus FK are active in vitro against the major invasive fungal pathogens but they are also immunosuppressive in the host limiting therapeutic effectiveness The objective of this Phase I SBIR project is to identify non immunosuppressive CsA analogs with antifungal activity against clinically relevant fungal species either active alone or in combination with existing antifungal drugs The project is enabled by one of the largest known collections of CsA analogs bearing modifications at multiple sites that introduce both chemical and biological diversity Using that collection preliminary studies have already defined CsA analogs that have substantially lower or no immunosuppressive action yet retain effective antifungal activity in vitro against the two most common pathogenic fungi Candida albicans and Aspergillus fumigatus This proposal will identify additional CsA analogs with low immunosuppression and high antifungal potency against both species including clinically relevant drug resistant strains Active analogs will be tested against difficult to treat species such as C krusei C glabrata and A terreus to bette define the spectrum of antifungal activity Active compounds will also be evaluated for in vitro cytotoxicity and metabolic stability to identify up to candidates suitable for future testing i animal efficacy models at the outset of Phase II Additional Phase II studies will include testing against a wider spectrum of clinical isolates evaluation against biofilms and chemical optimization for selection of preclinical lead candidate s for ultimate clinical evaluation PUBLIC HEALTH RELEVANCE Invasive fungal infections are a leading cause of death in immunocompromised patients and are conservatively estimated to cost the US healthcare system $ billion annually Current antifungal drugs have limited clinical efficacy with success rates of against the two most common infections This study will identify new drug candidates that block a fungal process required for invasive fungi to survive in humans


Patent
Scynexis | Date: 2013-10-21

Cyclosporin derivatives, methods of manufacturing the cyclosporin derivatives and methods for treating subjects infected with certain viruses, including hepatitis virus or HIV by administering the cyclosporin derivatives are described.


Patent
Scynexis | Date: 2016-01-14

SCY-078 is a glucan synthase inhibitor with antimicrobial activity. Novel salts and polymorph forms of SCY-078 are disclosed herein. The disclosure also relates to pharmaceutical compositions, methods of use, and methods of preparing the novel salts and polymorphs of SCY-078.


Patent
Scynexis | Date: 2013-10-21

Cyclosporin derivatives, methods of manufacturing the cyclosporin derivatives and methods for treating subjects infected with certain viruses, including hepatitis virus or HIV by administering the cyclosporin derivatives are described.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.29K | Year: 2014

DESCRIPTION (provided by applicant): Myopathies and other clinical disorders arising from genetic abnormalities of the mitochondrial respiratory chain collectively affect as many as 1 in 8000 individuals, representing in aggregate a significant disease burden, even though the specific underlying genetic lesions are each quite rare. Despite the need for therapeutic strategies to prevent or slow the progression of these often disabling and at times fatal genetic diseases, existing treatment options for mitochondrial disease patients are limited primarily to symptom management. Genetic and clinical heterogeneity make diagnosis, treatment, and therapeutic discovery for these diseases challenging, and disease-modifying treatments remain elusive for the majority of mitochondrial disorders. Inhibition of specific cellular pathology common to multiple mitochondrial diseases could complement approaches targeting the primary genetic defects in individual disorders, and contribute to combination strategies for redu

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