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1.
J Med Chem ; 66(17): 12544-12558, 2023 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-37656698

RESUMEN

Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation to cysteine, it is achieved by ring hydrolysis of the succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that the succinimide ring open form is in equilibrium with the ring closed succinimide. Bromoacetamide (BrAc) was identified as the optimal replacement, as it affords stable attachment of the drug-linker to the antibody while completely removing the undesired ring open-closed equilibrium. Additionally, BrAc also offers multiple benefits over maleimide, especially with respect to homogeneity of the ADC structure. In combination with a short, hydrophilic linker and phosphate prodrug on the payload, this afforded a stable ADC (ABBV-154) with the desired properties to enable long-term stability to facilitate subcutaneous self-administration.


Asunto(s)
Inmunoconjugados , Profármacos , Receptores de Glucocorticoides , Inhibidores del Factor de Necrosis Tumoral , Anticuerpos , Profármacos/farmacología , Glucocorticoides , Maleimidas , Inmunoconjugados/farmacología
2.
Regul Toxicol Pharmacol ; 102: 53-64, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30562600

RESUMEN

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model. Such results present challenges in generating an overall mutagenicity prediction and highlight the importance of performing a thorough expert review. The following paper reviews pharmaceutical and regulatory experiences handling such situations. The paper also presents an analysis of proprietary data to help understand the likelihood of misclassifying a mutagenic impurity as non-mutagenic based on different combinations of (Q)SAR results. This information may be taken into consideration when supporting the (Q)SAR results with an expert review, especially when out-of-domain results are generated during a (Q)SAR evaluation.


Asunto(s)
Contaminación de Medicamentos , Guías como Asunto , Mutágenos/clasificación , Relación Estructura-Actividad Cuantitativa , Industria Farmacéutica , Agencias Gubernamentales , Mutágenos/toxicidad , Medición de Riesgo
3.
Regul Toxicol Pharmacol ; 77: 13-24, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26877192

RESUMEN

The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript.


Asunto(s)
Pruebas de Carcinogenicidad/métodos , Daño del ADN , Minería de Datos/métodos , Mutagénesis , Pruebas de Mutagenicidad/métodos , Mutágenos/toxicidad , Toxicología/métodos , Animales , Pruebas de Carcinogenicidad/normas , Simulación por Computador , Bases de Datos Factuales , Adhesión a Directriz , Guías como Asunto , Humanos , Modelos Moleculares , Estructura Molecular , Pruebas de Mutagenicidad/normas , Mutágenos/química , Mutágenos/clasificación , Formulación de Políticas , Relación Estructura-Actividad Cuantitativa , Medición de Riesgo , Toxicología/legislación & jurisprudencia , Toxicología/normas
4.
J Am Chem Soc ; 131(11): 3840-1, 2009 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-19249829

RESUMEN

A convergent synthesis of the marine natural product (+)-peloruside has been reported. This target has been assembled through the successive application of two methyl ketone boron aldol addition reactions to the latent C(7)-C(11) dialdehyde synthon. This approach afforded a 22-step synthesis of this natural product. The influence of resident stereocenters on aldol reaction diastereoselection has been examined in detail.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Lactonas/síntesis química , Alcoholes , Aldehídos , Animales , Productos Biológicos/síntesis química , Poríferos/química , Estereoisomerismo , Moduladores de Tubulina/síntesis química
5.
Org Lett ; 11(3): 593-6, 2009 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-19113896

RESUMEN

A close structural analogue of bryostatin 1, which differs from bryostatin 1 only by the absence of the C(30) carbomethoxy group (on the C(13) enoate of the B-ring), has been prepared by total synthesis. Biological assays reveal a crucial role for substitution in the bryostatin 1 A-ring in conferring those responses which are characteristic of bryostatin 1 and distinct from those observed with PMA.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/síntesis química , Brioestatinas/química , Ésteres del Forbol/química , Antineoplásicos/farmacología , Brioestatinas/síntesis química , Brioestatinas/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Ésteres del Forbol/farmacología , Relación Estructura-Actividad
6.
Org Lett ; 8(17): 3667-70, 2006 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-16898787

RESUMEN

[reaction: see text] The synthesis of a C1-C13 A-ring subunit of bryostatin 1 is detailed. The key features of the approach include the convergent fragment assembly with a highly stereoselective construction of the C7-C8 bond indicated above.


Asunto(s)
Macrólidos/síntesis química , Animales , Brioestatinas , Briozoos/química , Macrólidos/química , Estructura Molecular
7.
Tetrahedron Lett ; 47(47): 8267-8270, 2006 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-17404602

RESUMEN

An expeditious assembly of a C(1)-C(16) subunit of bryostatin 1 is described. A pyran annulation reaction was utilized to form the B-ring by reaction of a hydroxy-allylsilane with a fully elaborated A-ring subunit. This annulation process proceeded with complete diastereoselectivity and in excellent isolated yield despite the presence of potentially sensitive functionality in the A-ring segment.

8.
Org Lett ; 4(21): 3687-90, 2002 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-12375919

RESUMEN

[reaction: see text] Previously unknown intramolecular Baylis-Hillman and Morita reactions involving cyclization of an unsaturated thiol ester onto a pendant aldehyde function are reported. These can be used successfully for the preparation of both cyclopentenols and cyclohexenols, but the results are very sensitive to substrate and precise reaction conditions.


Asunto(s)
Aldehídos/química , Ésteres/química , Compuestos de Sulfhidrilo/química
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