Search

Your search keyword '"Higley, Helen"' showing total 2 results
Start Over Author "Higley, Helen" Publisher elsevier science ltd
2 results on '"Higley, Helen"'

1. The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor.

Author

Naidu BN, Walker MA, Sorenson ME, Ueda Y, Matiskella JD, Connolly TP, Dicker IB, Lin Z, Bollini S, Terry BJ, Higley H, Zheng M, Parker DD, Wu D, Adams S, Krystal MR, and Meanwell NA

Subjects
Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, HIV Integrase Inhibitors chemical synthesis, HIV Integrase Inhibitors chemistry, Humans, Microbial Sensitivity Tests, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Structure-Activity Relationship, Thiazines chemical synthesis, Thiazines chemistry, Anti-HIV Agents pharmacology, Drug Discovery, HIV drug effects, HIV Integrase metabolism, HIV Integrase Inhibitors pharmacology, Pyrimidines pharmacology, Pyrimidinones pharmacology, Thiazines pharmacology
Abstract

BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
Full Text
View/download PDF

2. Synthesis and evaluation of C2-carbon-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as HIV-1 integrase inhibitors.

Author

Naidu BN, Sorenson ME, Patel M, Ueda Y, Banville J, Beaulieu F, Bollini S, Dicker IB, Higley H, Lin Z, Pajor L, Parker DD, Terry BJ, Zheng M, Martel A, Meanwell NA, Krystal M, and Walker MA

Subjects
Amides chemical synthesis, Amides pharmacokinetics, Animals, HIV Integrase metabolism, HIV Integrase Inhibitors chemistry, HIV Integrase Inhibitors pharmacokinetics, HIV-1 drug effects, Half-Life, Heterocyclic Compounds chemistry, Humans, Male, Pyrimidines chemistry, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Amides chemistry, HIV Integrase chemistry, HIV Integrase Inhibitors chemical synthesis, HIV-1 enzymology
Abstract

Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2015
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results