ACS Medicinal Chemistry Letters最新文献

In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of Mycobacterium tuberculosis DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of M. tuberculosis DNA gyrase in complex with DNA and compound 5 from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound 5 is a promising M. tuberculosis DNA gyrase inhibitor, with an IC₅₀ for M. tuberculosis gyrase of 0.096 μM, and it has potent activity against M. tuberculosis, with an IC₅₀ of 0.165 μM.

The invention in this patent application relates to 1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one derivatives represented generally by formula 1. These compounds are inhibitors of the E3 ubiquitin ligase, casitas B-lineage lymphoma proto-oncogene-b (CBL-B), and may be useful for the treatment of immunosuppression-associated diseases and disorders such as cancer and chronic viral infections.

The invention in this patent application relates to 1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one derivatives represented generally by formula 1. These compounds are inhibitors of the E3 ubiquitin ligase, casitas B-lineage lymphoma proto-oncogene-b (CBL-B), and may be useful for the treatment of immunosuppression-associated diseases and disorders such as cancer and chronic viral infections.

The invention in this patent application relates to N-(2-amino-2-oxoethyl)heteroarylcarboxamide derivatives, represented herein generally by formula 1. These compounds are inhibitors of the binding of interleukin 17A (IL-17A) with its receptor IL-17RA and may potentially be used for the treatment of diseases or disorders associated with IL-17A activity, which include psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis, cancer, and neurodegenerative disorders.

The invention in this patent application relates to N-(2-amino-2-oxoethyl)heteroarylcarboxamide derivatives, represented herein generally by formula 1. These compounds are inhibitors of the binding of interleukin 17A (IL-17A) with its receptor IL-17RA and may potentially be used for the treatment of diseases or disorders associated with IL-17A activity, which include psoriasis, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis, cancer, and neurodegenerative disorders.

Provided herein are novel triazines as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating multiple diseases, and processes for preparing such compounds.

Provided herein are novel triazines as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating multiple diseases, and processes for preparing such compounds.

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu₅) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified VU6043653, a highly brain penetrant and selective mGlu₅ NAM which displayed moderate potency against both human and rat mGlu₅. Moreover, VU6043653 has overall improved pharmacological and drug metabolism and pharmacokinetic profiles when compared to its predecessor compounds. Most notably, VU6043653 exhibits low predicted human hepatic clearance, a clean cytochrome P450 profile, and minimal inhibition of the dopamine transporter.

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu₅) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified VU6043653, a highly brain penetrant and selective mGlu₅ NAM which displayed moderate potency against both human and rat mGlu₅. Moreover, VU6043653 has overall improved pharmacological and drug metabolism and pharmacokinetic profiles when compared to its predecessor compounds. Most notably, VU6043653 exhibits low predicted human hepatic clearance, a clean cytochrome P450 profile, and minimal inhibition of the dopamine transporter.

Provided herein are novel pyrrolidines as main protease inhibitors, pharmaceutical compositions, use of such compounds in treating viral infections, in particular, coronavirus infections, and processes for preparing such compounds.