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Amit S. Kalgutkar

Bio: Amit S. Kalgutkar is an academic researcher from Genentech. The author has contributed to research in topics: Drug metabolism & Liver injury. The author has an hindex of 2, co-authored 4 publications receiving 422 citations.

Papers
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01 Jan 2013
TL;DR: An algorithm was devised for use in drug discovery/early development to assess cytochrome P450 inhibitory potential of drug metabolites and the propensity to cause a clinically relevant DDI.
Abstract: Understanding drug-drug interactions (DDIs) is a key component of clinical practice ensuring patient safety and efficacy of medicines. The role of drug metabolites in DDIs is a developing area of science, and has been recently highlighted in a draft regulatory guidance. The guidance states that metabolites representing ‡25% of the parent drug’s area under the plasma concentration/time curve and/or >10% of exposure of total drug-related material should trigger in vitro characterization of metabolites for cytochrome P450 inhibition and propensity for DDIs. The relationship between in vitro cytochrome P450 inhibitory potency, systemic exposure, and DDI potential of drug metabolites was examined using the Pfizer development database to identify compounds with pre-existing in vivo biotransformation data, where circulating metabolites were identified in humans. The database yielded 33 structurally diverse compounds with collectively 115 distinct circulating metabolites. Of these, 52% (60/115) achieved exposures >25% of parent drug levels as judged from mass balance/metabolite identification studies. It was noted that 14 metabolite standards for 12 parent drugs had been synthesized, monitored in clinical studies, and examined for cytochrome P450 inhibition. For the 14 metabolite/parent drug pairs, no clinically relevant DDIs were expected to occur against the major human cytochrome P450 isoforms. A review of the literature for parent/metabolite DDI information was also conducted to examine trends using a larger data set. Leveraging the analysis of both internal and literature-based data sets, an algorithm was devised for use in drug discovery/early development to assess cytochrome P450 inhibitory potential of drug metabolites and the propensity to cause a clinically relevant DDI.

Cited by
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Journal ArticleDOI
TL;DR: The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.
Abstract: The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of 'click chemistry' due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.

983 citations

Journal ArticleDOI
TL;DR: The Methylation Effect in Medicinal Chemistry Eliezer J. Barreiro,* Arthur E. K€ummerle, and Carlos A. M. Fraga Laborat orio de Avaliac-~ao e Síntese de Subst̂ancias Bioativas (LASSBio), Faculdade de Farm acia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universit aria.
Abstract: The Methylation Effect in Medicinal Chemistry Eliezer J. Barreiro,* Arthur E. K€ummerle, and Carlos A. M. Fraga Laborat orio de Avaliac-~ao e Síntese de Subst̂ancias Bioativas (LASSBio), Faculdade de Farm acia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universit aria, CP 68.006, 21941-902 Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Farmacologia e Química Medicinal, Instituto de Cîencias Biom edicas, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil

572 citations

Journal ArticleDOI
TL;DR: The present work aims to summarize the current approaches adopted for the synthesis of the 1,2,3-triazole and medicinal significance of these architectures as a lead structure for the discovery of drug molecules such as COX-1/COX-2 inhibitors, HIV protease inhibitors, CB1 cannabinoid receptor antagonist and much more which are in the pipeline of clinical trials.

563 citations

Journal ArticleDOI
TL;DR: A number of more complex P450 reactions also occur, and these can be understood largely in the context of the basic chemical mechanisms and subsequent rearrangements.

401 citations

Journal ArticleDOI
TL;DR: This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Abstract: Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.

374 citations