Elucidating the Pathways of Degradation of Denagliptin

Joshi, Biren K.; Ramsey, Beverly; Johnson, Byron S.; Patterson, Daniel E.; Powers, Jeremiah D.; Facchine, Kevin L.; Osterhout, Martin H.; Leblanc, Michael P.; Bryant-Mills, Renetta; Copley, Royston C. B.; Sides, Scott L.

doi:10.1002/jps.22069

Cited by 7 publications

(4 citation statements)

References 27 publications

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“…The nitrile group in 9 is activated by the presence of the ortho-pyrimidine and para-fluoro substituents-this favors its intramolecular attack by the amine to form an amidine intermediate, which hydrolyzes into the phenanthridinone product (Figure 3). Based on this observation and literature precedent, [21][22][23][24][25][26][27][28][29][30] we believe that the same reaction mechanism occurs during the DECL synthesis to generate the phenanthridinone structure as the major product on DNA.…”

Section: Validation and Synthesis Of Pdcl2 Selection Hitssupporting

confidence: 58%

“…The nitrile group in 9 is activated by the presence of the ortho ‐pyrimidine and para ‐fluoro substituents—this favors its intramolecular attack by the amine to form an amidine intermediate, which hydrolyzes into the phenanthridinone product (Figure 3). Based on this observation and literature precedent, 21–30 we believe that the same reaction mechanism occurs during the DECL synthesis to generate the phenanthridinone structure as the major product on DNA. Inspired by the unexpected phenanthridinone formation, we prepared CDD‐2377 (Scheme 1B) as the C2 truncated version of CDD‐2364 in a similar manner for structural activity relationship studies.…”

Section: Resultsmentioning

confidence: 53%

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Advancing ASMS with LC‐MS/MS for the discovery of novel PDCL2 ligands from DNA‐encoded chemical library selections

Belabed

Wang

et al. 2022

Andrology

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Background: A safe, effective, and reversible nonhormonal male contraceptive drug is greatly needed for male contraception as well as for circumventing the side effects of female hormonal contraceptives. Phosducin-like 2 (PDCL2) is a testis-specific phosphoprotein in mice and humans. We recently found that male PDCL2 knockout mice are sterile due to globozoospermia caused by impaired sperm head formation, indicating that PDCL2 is a potential target for male contraception. Herein, our study for the first time developed a biophysical assay for PDCL2 allowing us to screen a series of small molecules, to study structure-activity relationships, and to discover two PDCL2 binders with novel chemical structure.Objective: To identify a PDCL2 ligand for therapeutic male contraception, we performed DNA-encoded chemical library (DECL) screening and off-DNA hit validation using a unique affinity selection mass spectrometry (ASMS) biophysical profiling strategy. Materials and methods: We employed the screening process of DECL, which contains billions of chemically unique DNA-barcoded compounds generated through individual sequences of reactions and different combinations of functionalized building blocks. The structures of the PDCL2 binders are proposed based on the sequencing analysis of the DNA barcode attached to each individual DECL compound. The proposed structure is synthesized through multistep reactions. To confirm and determine binding affinity between the DECL identified molecules and PDCL2, we developed an ASMS assay that incorporates liquid chromatography with tandem mass spectrometry (LC-MS/MS).Results: After a screening process of PDCL2 with DECLs containing >440 billion compounds, we identified a series of hits. The selected compounds were synthesized as Hassane Belabed, Yong Wang, and Zhifeng Yu contributed equally to this work.

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Section: Validation and Synthesis Of Pdcl2 Selection Hitssupporting

confidence: 58%

Section: Resultsmentioning

confidence: 53%

Advancing ASMS with LC‐MS/MS for the discovery of novel PDCL2 ligands from DNA‐encoded chemical library selections

Belabed

Wang

et al. 2022

Andrology

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“…The additional stability enhancement is unclear at this point; X-ray analysis (data not shown) of the drug coated pellet reveals the same crystal structure so a change in the molecular orientation of the drug did not occur. Based on prior stress testing of the model DPP-IV inhibitor, it could be hypothesized that the Wurster coating process with hypromellose allows the amino group to be more likely to remain protonated and trans to the cyano group thus improving stability (10). While the exact mechanism of stability enhancement is unknown, it was interesting to find that a similar result was obtained when using the fluid bed Wurster coating process to stabilize a chemically unstable compound in a fixed dose combination tablet.…”

Section: Optimization Of Drug Layered Pellet Seal Coatmentioning

confidence: 99%

Stability Enhancement of Drug Layered Pellets in a Fixed Dose Combination Tablet

Burke

Cook

et al. 2013

AAPS PharmSciTech

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Abstract. The purpose of this research was to develop a stable fixed dose combination tablet for a model DPP-IV inhibitor and metformin hydrochloride. The dipeptidyl peptidase IV (DPP-IV) inhibitor was particularly challenging to formulate due to its significant chemical instability and moisture sensitivity. Various formulation strategies were investigated and placed on accelerated stability to determine the lead approach and critical quality attributes. The lead formulation investigated was a drug layered pellet containing the DPP-IV inhibitor, which was further coated with various seal coats and moisture barriers, then compressed into a tablet with compression aids and granulated metformin hydrochloride. The investigations revealed that the drug layered pellets compressed into a fixed dose combination tablet yielded a unique stability enhancement. The stability was highly dependent on the final tablet water content and could be further improved by the addition of moisture barrier coatings. A fundamental understanding of the key critical quality attributes for the fixed dose combination product containing a DPP-IV inhibitor and metformin hydrochloride as an oral solid dosage form were established. This research identified a formulation approach to enable a successful commercial product to be developed.

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“…Em desenvolvimento as seguintes drogas: teneligliptina, gemigliptina, trelagliptina, gosogliptina, xagliptina, dutogliptina, denagliptina e retagliptina (38)(39)(40)(41)(42)(43)(44)(45). Elas aumentam o efeito incretínico in vitro, prolongando a ação do GLP-1 nativo (46).…”

Section: Escolha Da Segunda Opção Na Terapia Combinada Após a Falênciunclassified

Eficácia em longo prazo das gliflozinas versus gliptinas no tratamento do diabetes mellitus tipo 2 após falência da metformina como monoterapia: revisão sistemática e metanálise em rede

Zilli¹

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AGRADECIMENTOSAgradeço ao meu orientador, Prof. Dr. Fabiano Pinheiro, pela sua dedicação, por sempre estar disposto a colaborar.Ao Dr. Renato Baena, pelo seu tempo, conhecimento e fins de semana! A Rodrigo Brandão, Marcelo Silva, Anna Buehler que me ajudaram nas etapas iniciais da minha tese, obrigado por disporem de seu tempo e conhecimento.A Cochrane do Brasil, onde tive oportunidade de aprender sobre revisão sistemática.A Claudio Tavares por me ajudar com os pequenos e importantes detalhes da minha tese.À minha família, amigos e pacientes! Prometo dedicar mais de mim a vocês agora. RESUMOA metformina é a droga de escolha no tratamento inicial do diabetes mellitus tipo 2 (DM2). Não existe consenso na literatura sobre qual seria a segunda melhor opção terapêutica após a falência desta em longo prazo. Objetivo: avaliar a eficácia em longo prazo de gliflozinas e gliptinas após a falência do tratamento primário com metformina no DM2. Material e métodos: foi realizada uma revisão sistemática para o maior tempo de tratamento nas bases de dados bases Embase, Pubmed (via Medline), Lilacs e Cochrane Library e metanálise em rede com as sulfoniluréias (glimepirida e glipizida) como meta comparador. Desfechos: eficácia da medicação (valor final da HbA1c e porcentagem de pacientes com HbA1c < 7%), variação de peso e frequência de pacientes com hipoglicemia. Resultados: O maior tempo de segmento foi de quatro anos. Foram selecionados um artigo com empagliflozina, um artigo com dapagliflozina e um artigo com saxagliptina com dados faltantes. Após um ano de tratamento, mais de 50% dos pacientes estavam com HbA1c > 7%. O perfil de eficácia em quatro anos da empagliflozina (23%) foi melhor que da dapagliflozina (5%) e saxagliptina (7%), porém com valores de HbA1c não estatisticamente significantes (7,4 e 7,3% entre as gliflozinas), sem dados para a saxagliptina. Entretanto, a empagliflozina foi superior à glimepirida no período de quatro anos (diferença média padronizada/DMP: 0,40, intervalo de confiança/IC95%: 0,23-0,56). A variação de peso permaneceu estável após um ano de tratamento, com vantagem em quatro anos para a empa (DMP: 1,56, IC95%: 1,23-1,88). A frequência de pacientes com hipoglicemia não diferiu entre empagliflozina e dapagliflozina (razão de chances: 1,53, IC95%: 0,80-2,91) e foi significativamente menor do que em relação às sulfoniluréias. Conclusões: a falência da segunda terapia com gliflozinas ocorre em menos de um ano de tratamento (> 50% dos pacientes com HbA1c > 7%). A empagliflozina obteve um controle glicêmico melhor em relação às sulfoniluréias, porém semelhante à dapagliflozina. A perda de peso foi mantida por quatro anos, com superioridade para empagliflozina. Houve uma baixa frequência de hipoglicemia nas gliflozinas em comparação com as sulfoniluréias.Mais estudos são necessários para avaliar a eficácia de gliptinas e gliflozinas em longo prazo, após a falência terapêutica com metformina. Descritores ABSTRACTMetformin is the first-choice treatment in people with type 2 diabetes (TD2). There is no...

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Elucidating the Pathways of Degradation of Denagliptin

Cited by 7 publications

References 27 publications

Advancing ASMS with LC‐MS/MS for the discovery of novel PDCL2 ligands from DNA‐encoded chemical library selections

Advancing ASMS with LC‐MS/MS for the discovery of novel PDCL2 ligands from DNA‐encoded chemical library selections

Stability Enhancement of Drug Layered Pellets in a Fixed Dose Combination Tablet

Eficácia em longo prazo das gliflozinas versus gliptinas no tratamento do diabetes mellitus tipo 2 após falência da metformina como monoterapia: revisão sistemática e metanálise em rede

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