12 research outputs found
Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery
Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules
Identification of Amides as Carboxylic Acid Surrogates for Quinolizidinone-Based M<sub>1</sub> Positive Allosteric Modulators
Selective activation of the M<sub>1</sub> muscarinic
receptor via positive allosteric modulation represents an approach
to treat the cognitive decline in patients with Alzheimer's disease.
A series of amides were examined as a replacement for the carboxylic
acid moiety in a class of quinolizidinone carboxylic acid M<sub>1</sub> muscarinic receptor positive allosteric modulators, and leading
pyran <b>4o</b> and cyclohexane <b>5c</b> were found to
possess good potency and in vivo efficacy
MK-7622: A First-in-Class M<sub>1</sub> Positive Allosteric Modulator Development Candidate
Identification
of ligands that selectively activate the M<sub>1</sub> muscarinic
signaling pathway has been sought for decades to treat
a range of neurological and cognitive disorders. Herein, we describe
the optimization efforts focused on addressing key physicochemical
and safety properties, ultimately leading to the clinical candidate
MK-7622, a highly selective positive allosteric modulator of the M<sub>1</sub> muscarinic receptor that has entered Phase II studies in
patients with Alzheimer’s disease
Characterization of new potential anticancer drugs designed to overcome glutathione transferase mediated resistance
10.1021/mp2000692Molecular Pharmaceutics851698-1708MPOH