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2.
J Med Chem ; 67(4): 2369-2378, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38335279

ABSTRACT

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance), with good in vitro-to-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Cell Differentiation , Disclosure , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Antiviral Agents/pharmacology
3.
Org Lett ; 22(11): 4196-4200, 2020 06 05.
Article in English | MEDLINE | ID: mdl-32437168

ABSTRACT

A novel "non-aromatic pool" synthetic strategy for the synthesis of benzofuran-based natural products via oxidative haloaromatization of enones is reported. This approach is successfully applied in the first total synthesis of the natural product aspergillusene B. In comparison with a separately executed "aromatic pool" synthesis, the "non-aromatic pool" protocol demonstrates equivalent efficiency but offers a much higher degree of modularity.


Subject(s)
Benzofurans/chemistry , Biological Products/chemical synthesis , Ketones/chemistry , Biological Products/chemistry , Halogenation , Molecular Structure , Stereoisomerism
4.
Synthesis (Stuttg) ; 50(22): 4359-4368, 2018 Nov.
Article in English | MEDLINE | ID: mdl-31061542

ABSTRACT

A short enantioselective formal synthesis of the antibiotic natural product platencin is reported. Key steps in the synthesis include enantioselective decarboxylation alkylation, aldehyde/olefin radical cyclization, and regioselective aldol cyclization.

5.
Beilstein J Org Chem ; 13: 564-570, 2017.
Article in English | MEDLINE | ID: mdl-28405236

ABSTRACT

Cu- and Pd-catalyzed arylation of aminocholanes has been described for the first time. While this Cu-catalyzed protocol provides high yields in reactions of aminocholanes with iodoarenes, Pd catalysis was found to be preferable for the reactions of aminocholanes with dichloroanthraquinones. UV-vis titration of bis(cholanylamino)anthraquinones with a series of cations demonstrated their high binding affinity to Cu2+, Al3+, and Cr3+.

6.
Org Lett ; 18(19): 5010-5013, 2016 10 07.
Article in English | MEDLINE | ID: mdl-27647101

ABSTRACT

A novel synthetic approach for the synthesis of bioactive phenolic natural products is reported. This strategy highlights the power of halogenative aromatization reactions recently developed in our group for preparing densely functionalized arenes in a controlled fashion. Five natural products related by an aromatic core and a farnesyl side chain are synthesized. In contrast to prior methods, this synthesis features high efficiency and generality that permits preparation of targets in gram-scale quantities.

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