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1.
Drug Metab Rev ; : 1-33, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38989688

RESUMO

This annual review marks the eighth in the series starting with Baillie et al. (2016) Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation. Its format is to highlight important aspects captured in synopsis followed by a commentary with relevant figure and references.

2.
Drug Metab Rev ; 55(4): 301-342, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37737116

RESUMO

This annual review is the eighth of its kind since 2016 (Baillie et al. 2016, Khojasteh et al. 2017, Khojasteh et al. 2018, Khojasteh et al. 2019, Khojasteh et al. 2020, Khojasteh et al. 2021, Khojasteh et al. 2022). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation.


Assuntos
Biotransformação , Humanos
3.
Drug Metab Rev ; 55(4): 267-300, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37608698

RESUMO

With the 50th year mark since the launch of Drug Metabolism and Disposition journal, the field of drug metabolism and bioactivation has advanced exponentially in the past decades (Guengerich 2023).This has, in a major part, been due to the continued advances across the whole spectrum of applied technologies in hardware, software, machine learning (ML), and artificial intelligence (AI). LC-MS platforms continue to evolve to support key applications in the field, and automation is also improving the accuracy, precision, and throughput of these supporting assays. In addition, sample generation and processing is being aided by increased diversity and quality of reagents and bio-matrices so that what is being analyzed is more relevant and translatable. The application of in silico platforms (applied software, ML, and AI) is also making great strides, and in tandem with the more traditional approaches mentioned previously, is significantly advancing our understanding of bioactivation pathways and how these play a role in toxicity. All of this continues to allow the area of bioactivation to evolve in parallel with associated fields to help bring novel or improved medicines to patients with urgent or unmet needs.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.


Assuntos
Inteligência Artificial , Aprendizado de Máquina , Humanos , Espectrometria de Massas
4.
Pharm Res ; 40(8): 1901-1913, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37280472

RESUMO

PURPOSE: After single oral dosing of the glycine reuptake transporter (GlyT1) inhibitor, iclepertin (BI 425809), a single major circulating metabolite, M530a, was identified. However, upon multiple dosing, a second major metabolite, M232, was observed with exposure levels ~ twofold higher than M530a. Studies were conducted to characterize the metabolic pathways and enzymes responsible for formation of both major human metabolites. METHODS: In vitro studies were conducted with human and recombinant enzyme sources and enzyme-selective inhibitors. The production of iclepertin metabolites was monitored by LC-MS/MS. RESULTS: Iclepertin undergoes rapid oxidation to a putative carbinolamide that spontaneously opens to an aldehyde, M528, which then undergoes reduction by carbonyl reductase to the primary alcohol, M530a. However, the carbinolamide can also undergo a much slower oxidation by CYP3A to form an unstable imide metabolite, M526, that is subsequently hydrolyzed by a plasma amidase to form M232. This difference in rate of metabolism of the carbinolamine explains why high levels of the M232 metabolite were not observed in vitro and in single dose studies in humans, but were observed in longer-term multiple dose studies. CONCLUSIONS: The long half-life iclepertin metabolite M232 is formed from a common carbinolamine intermediate, that is also a precursor of M530a. However, the formation of M232 occurs much more slowly, likely contributing to its extensive exposure in vivo. These results highlight the need to employ adequate clinical study sampling periods and rigorous characterization of unexpected metabolites, especially when such metabolites are categorized as major, thus requiring safety assessment.


Assuntos
Inibidores Enzimáticos , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida , Meia-Vida , Inibidores Enzimáticos/metabolismo , Redes e Vias Metabólicas , Microssomos Hepáticos/metabolismo
5.
Drug Metab Rev ; 54(3): 207-245, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35815654

RESUMO

Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al. (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article). Based on the selected articles, this review was categorized into three sections: (1) new modalities biotransformation, (2) drug discovery biotransformation, and (3) drug development biotransformation (Table 1).


Assuntos
Descoberta de Drogas , Biotransformação , Humanos , Inativação Metabólica
6.
Drug Metab Rev ; 54(3): 246-281, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35876116

RESUMO

This year's review on bioactivation and reactivity began as a part of the annual review on biotransformation and bioactivation led by Cyrus Khojasteh (see references). Increased contributions from experts in the field led to the development of a stand alone edition for the first time this year focused specifically on bioactivation and reactivity. Our objective for this review is to highlight and share articles which we deem influential and significant regarding the development of covalent inhibitors, mechanisms of reactive metabolite formation, enzyme inactivation, and drug safety. Based on the selected articles, we created two sections: (1) reactivity and enzyme inactivation, and (2) bioactivation mechanisms and safety (Table 1). Several biotransformation experts have contributed to this effort from academic and industry settings.[Table: see text].


Assuntos
Microssomos Hepáticos , Biotransformação , Humanos , Microssomos Hepáticos/metabolismo
7.
Rapid Commun Mass Spectrom ; 35(16): e9131, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34038984

RESUMO

RATIONALE: BI 605906 undergoes a collision-induced dissociation (CID) fragmentation resulting in the loss of methylsulfinic acid and butadiene to produce a corresponding imine. The fragmentation is hypothesized to occur via inductive cleavage of the C-S bond, generating a six-membered cyclic ene, followed by the retro-Diels-Alder (RDA) reaction. The aim of this study was to provide mechanistic evidence for the proposed fragmentation by investigating the CID spectra of BI 605906 and other alkylsulfonyl piperidine- and piperazine-containing compounds. METHODS: The positive electrospray ionization tandem mass spectrometric (ESI+ -MS/MS) fragmentations of BI 605906, D9 -BI 605906, GK02935, GK02942, ketoconazole, terazosin, and homopiperazine were investigated. Additionally, incubations of BI 605906 and GK02942 in human liver microsomes (HLM) preparations were conducted. Metabolite identification experiments were performed following these incubations to investigate corresponding in vitro metabolism. RESULTS: BI 605906, D9 -BI 605906, GK02935, and GK02942 demonstrated the same fragmentation pattern by generating a respective imine ion, supporting the hypothesized inductive cleavage and subsequent RDA mechanism. Ketoconazole and terazosin, which contain either an N-acetyl or tetrahydrofuranyl piperazine group, respectively, did not demonstrate this mechanism, notably because they do not have the alkylsulfonyl moiety as a good leaving group. Although homopiperazine contains an arylsulfonyl diazepane group, and the initial step produced an unsaturated diazepane ring, the subsequent RDA reaction was unable to proceed due to the absence of a six-membered cyclic ene intermediate. Additionally, we identified oxidative metabolites of BI 605906 and GK02942 in HLM incubations utilizing the proposed fragmentation pattern. CONCLUSIONS: In the mass spectrometer, compounds containing alkylsulfonyl piperidine or piperazine groups can undergo inductive cleavage, leading to a six-membered cyclic ene intermediate. This intermediate will then form a corresponding imine ion via the RDA reaction. A practical application of this work is to utilize this fragmentation for elucidating structures of metabolites arising from parent compounds containing alkylsulfonyl piperidine or piperazine moieties.

8.
Drug Metab Dispos ; 46(6): 770-778, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29514826

RESUMO

BI 187004, an 11ß-hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N-methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite [N-methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O-methyltransferase (rhCOMT), histamine N-methyltransferase (rhHNMT), nicotinamide N-methyltransferase (rhNNMT), glycine N-methyltransferase (rhGNMT), and thiopurine S-methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro-α-methylbenzylamine (DCMB), an inhibitor of thiol S-methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N-methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N-methylation biotransformation and an HNMT-mediated regioselective N-methylation.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Metiltransferases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biotransformação/fisiologia , Criança , Pré-Escolar , Citosol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Metilação , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Proteínas Recombinantes/metabolismo , Compostos de Sulfidrila , Adulto Jovem
9.
Int J Toxicol ; 36(6): 440-448, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29130831

RESUMO

In a previously reported CD-1 mouse 2-year carcinogenicity study with the sodium glucose cotransporter-2 inhibitor empagliflozin, an increased incidence of renal tubular adenomas and carcinomas was identified only in the male high-dose group. Follow-up investigative studies have shown that the renal tumors in male high-dose mice were preceded by a number of renal degenerative/regenerative findings. Prior cross-species in vitro metabolism studies using microsomes identified an oxidative metabolite (M466/2) predominantly formed in the male mouse kidney and which spontaneously degrades to a metabolite (M380/1) and reactive 4-OH crotonaldehyde (CTA). In order to further evaluate potential modes of action for empagliflozin-associated male mouse renal tumors, we report here a series of in vitro investigative toxicology studies conducted to evaluate the cytotoxic and genotoxic potential of empagliflozin and M466/2. To assess the cytotoxic potential of empagliflozin and M466/2, a primary mouse renal tubular epithelial (mRTE) cell model was used. In mRTE cells, M466/2-derived in vitro 4-OH CTA exposure was cytotoxic, while empagliflozin was not cytotoxic or mitogenic. Empagliflozin and M466/2 were not genotoxic, supporting an indirect mode of action for empagliflozin-associated male mouse renal tumorigenesis. In conclusion, these in vitro data show that M466/2-derived 4-OH CTA exposure is associated with cytotoxicity in renal tubule cells and may be involved in promoting compound-related in vivo renal metabolic stress and chronic low-level renal injury, in turn supporting a nongenotoxic mode of tumor pathogenesis specific to the male mouse.


Assuntos
Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/toxicidade , Glucosídeos/metabolismo , Glucosídeos/toxicidade , Hipoglicemiantes/metabolismo , Hipoglicemiantes/toxicidade , Túbulos Renais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Compostos Benzidrílicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glucosídeos/química , Hipoglicemiantes/química , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Relação Estrutura-Atividade
10.
J Med Chem ; 54(13): 4365-77, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21634429

RESUMO

Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S proteasome, is remarkably effective against multiple myeloma (MM) but not against solid tumors. Dose-limiting adverse effects from "on target" inhibition of the proteasome in normal cells and tissues appear to be a key obstacle. Achieving efficacy against solid tumors therefore is likely to require making the inhibitor more selective for tumor tissue over normal tissues. The simplest strategy that might provide such tissue specificity would be to employ a tumor specific protease to release an inhibitor from a larger, noninhibitory structure. However, such release would necessarily generate an inhibitor with a free N-terminal amino group, raising a key question: Can short peptide boronic acids with N-terminal amino groups have the requisite properties to serve as warheads in prodrugs? Here we show that dipeptides of boroLeu, the smallest plausible candidates for the task, can indeed be sufficiently potent, cell-penetrating, cytotoxic, and stable to degradation by cellular peptidases to serve in this capacity.


Assuntos
Antineoplásicos/síntese química , Ácidos Borônicos/síntese química , Dipeptídeos/síntese química , Pró-Fármacos/síntese química , Inibidores de Proteassoma , Aminopeptidases/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Ciclização , Dipeptídeos/química , Dipeptídeos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
11.
J Med Chem ; 51(19): 6005-13, 2008 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-18783201

RESUMO

Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.


Assuntos
Ácidos Borônicos/administração & dosagem , Dipeptídeos/administração & dosagem , Inibidores de Serina Proteinase/administração & dosagem , Administração Oral , Animais , Glicemia/análise , Glicemia/metabolismo , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Linhagem Celular , Clonagem Molecular , Dipeptídeos/química , Dipeptídeos/farmacologia , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/isolamento & purificação , Inibidores da Dipeptidil Peptidase IV , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Dipeptidil Peptidases e Tripeptidil Peptidases/biossíntese , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Glucose/administração & dosagem , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Biblioteca de Peptídeos , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Fatores de Tempo
12.
J Med Chem ; 50(10): 2391-8, 2007 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-17458948

RESUMO

We describe here the epimerization-free synthesis and characterization of a new class of conformationally constrained lactam aminoboronic acid inhibitors of dipeptidyl peptidase IV (DPP IV; E.C. 3.4.14.5). These compounds have the advantage that they cannot undergo the pH-dependent cyclization prevalent in most dipeptidyl boronic acids that attenuates their potency at physiological pH. For example, D-3-amino-1-[L-1-boronic-ethyl]-pyrrolidine-2-one (amino-D-lactam-L-boroAla), one of the best lactam inhibitors of DPP IV, is several orders of magnitude less potent than L-Ala-L-boroPro, as measured by Ki values (2.3 nM vs 30 pM, respectively). At physiological pH, however, it is actually more potent than L-Ala-L-boroPro, as measured by IC50 values (4.2 nM vs 1400 nM), owing to the absence of the potency-attenuating cyclization. In an interesting and at first sight surprising reversal of the relationship between stereochemistry and potency observed with the conformationally unrestrained Xaa-boroPro class of inhibitors, the L-L diastereomers of the lactams are orders of magnitude less effective than the D-L lactams. However, this interesting reversal and the unexpected potency of the D-L lactams as DPP IV inhibitors can be understood in structural terms, which is explained and discussed here.


Assuntos
Alanina/análogos & derivados , Alanina/síntese química , Ácidos Bóricos/síntese química , Ácidos Borônicos/síntese química , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV , Lactamas/síntese química , Peptídeos/química , Pirrolidinonas/síntese química , Alanina/química , Biomimética , Ácidos Bóricos/química , Ácidos Borônicos/química , Humanos , Concentração de Íons de Hidrogênio , Lactamas/química , Modelos Moleculares , Pirrolidinonas/química , Estereoisomerismo , Relação Estrutura-Atividade
13.
J Org Chem ; 71(2): 512-9, 2006 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-16408958

RESUMO

[structure: see text] Six new N-acyl-boroGly derivatives, along with their N-acyl-boroSar analogues, have been synthesized by modification of conventional procedures. Structural characterization of these alpha-amidoboronic acids was accomplished by extensive use of 11B and 1H NMR spectroscopy. These compounds were prepared to determine the extent of intramolecular B-O dative bond formation within the context of a five-membered (:O=C-N-C-B) ring motif. It is shown that the formation of such dative bonds depends on the nature of the substituents at both the acyl carbon and the nitrogen atoms. Computational evidence from second-order Møller-Plesset perturbation theory is provided in support of these findings.


Assuntos
Amidas/química , Ácidos Borônicos/química , Amidas/síntese química , Ácidos Borônicos/síntese química , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular
14.
J Am Chem Soc ; 127(22): 8112-9, 2005 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-15926838

RESUMO

Many dipeptide boronic acids of the type H(2)N-X-Y-B(OH)(2) are potent protease inhibitors. Interest in these compounds as drugs for cancer, diabetes, and other diseases is growing. Because of the great mutual B-N affinity, cyclization through the N- and B-termini, forming six-membered rings, is a common occurrence at neutral pH and higher where the terminal amino group is unprotonated. Here we report the discovery that when X, the N-terminal amino acid, contains a side chain having a functional group with boron affinity and suitable geometry, additional cyclization in the form of bidentate intramolecular chelation or "autochelation" may occur, predominantly at mid pH. NMR studies of two compounds, l-Aspartyl-l-boroProline (Asp-boroPro) and l-Histidyl-l-boroProline (His-boroPro), are reported here from pH 0.5 to pH 12 by (1)H, (15)N, (13)C, and (11)B NMR. Both of these previously unreported autochelates contain two fused six-membered rings, cis-proline, chiral boron, and -NH(2)(+) protons in slow exchange with water, even at 25 degrees C and pH as high as 4. Using microscopic acid-base equilibrium constants, we show that at high pH (>8 for Asp-boroPro and >10 for His-boroPro) hydroxide competes with the side chains for boron, reducing the chelates from bidentate to monodentate. At low pH (<0.5), proton competition for N-terminal nitrogens causes both compounds to become noncyclic. High chelate stability causes a reduction of the apparent acidic dissociation constant of the protonated N-terminal amino group greater than eight units. In the His-boroPro autochelate, imidazolate anion is produced at the extraordinarily low pH value of approximately 9.


Assuntos
Ácidos Borônicos/química , Dipeptídeos/química , Prolina/análogos & derivados , Ácido Aspártico/análogos & derivados , Quelantes/química , Histidina/análogos & derivados , Concentração de Íons de Hidrogênio , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular/métodos , Inibidores de Proteases/química , Conformação Proteica
15.
J Chem Inf Comput Sci ; 42(2): 290-8, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11911698

RESUMO

Data for HIV-1 protease inhibitors (in vitro enzyme binding) were used as a training set to develop a QSAR model based on topological descriptors, including two hydrogen E-state indices, along with a molecular connectivity chi and a kappa shape index. A statistically satisfactory four-variable model was obtained for the 32 compounds in the training set, r2 = 0.86, s = 0.60, and q2 = 0.79, without the use of information from 3D geometries or detailed interaction energy calculations. The model was validated through the prediction of 15 compounds in the external test set, yielding a mean absolute error, MAE, = 0.82. Structure interpretation is given for each variable to assist in the design of new compounds. Structure features emphasized in the model include hydrogen bond donating ability, nonpolar groups, skeletal branching, and molecular globularity. On the basis of these statistical criteria, this E-state model may be considered useful for prediction of pIC50 values for new HIV-1 protease inhibitors.


Assuntos
Inibidores da Protease de HIV/metabolismo , Modelos Moleculares , Inibidores da Protease de HIV/química , Ligação de Hidrogênio , Relação Quantitativa Estrutura-Atividade
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