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Your search keyword '"Protack T"' showing total 2 results
Start Over Author "Protack T" Topic amides
2 results on '"Protack T"'

1. Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors.

Author

Peese KM, Naidu BN, Patel M, Li C, Langley DR, Terry B, Protack T, Gali V, Lin Z, Samanta HK, Zheng M, Jenkins S, Dicker IB, Krystal MR, Meanwell NA, and Walker MA

Subjects
Animals, Binding Sites, Catalytic Domain, Drug Resistance, Viral drug effects, HIV Integrase genetics, HIV Integrase metabolism, HIV Integrase Inhibitors metabolism, HIV Integrase Inhibitors pharmacology, HIV-1 drug effects, Half-Life, Heterocyclic Compounds, 3-Ring metabolism, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Molecular Dynamics Simulation, Mutation, Rats, Structure-Activity Relationship, Amides chemistry, HIV Integrase chemistry, HIV Integrase Inhibitors chemistry, HIV-1 enzymology, Heterocyclic Compounds, 3-Ring chemistry
Abstract

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Published
2020
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2. Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.

Author

Swidorski JJ, Liu Z, Sit SY, Chen J, Chen Y, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker IB, Meanwell NA, and Regueiro-Ren A

Subjects
Administration, Oral, Amides administration & dosage, Amides chemistry, Animals, Anti-HIV Agents administration & dosage, Benzoates administration & dosage, Benzoates chemistry, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Molecular Structure, Rats, Structure-Activity Relationship, Triterpenes administration & dosage, Triterpenes chemistry, Amides pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Benzoates pharmacology, HIV drug effects, HIV growth & development, Triterpenes pharmacology
Abstract

We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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