Soft spots, metabolic

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

INTEGRATED STRATEGIES FOR METABOLIC STABILITY DETERMINATION AND METABOLIC SOFT-SPOT CHARACTERIZATION... 

Figure 5.6 Structure of buspirone with areas susceptible to metabolic or chemical degradation highlighted for rapid visualization of the soft spots of the structure. (Courtesy of Milestone Development Services, Newtown, Pa., USA.)...

Toxicologically relevant biotransformation ( hot spots ) and positions of metabolic attack ( soft spots ) can be identified by structure elucidation of metabolites generated in vitro to support medicinal chemists in improving metabolic characteristics (Nassar and Talaat 2004b). In addition, structure elucidation of metabolites generated in vitro plays an important role because in vivo elucidation affords intense clean-up procedures besides the higher effort necessary to generate the samples. 

Trunzer M, Faller B, Zimmerlin A. Metabolic soft spot identification and compound optimization in early discovery phases using MetaSite and LC-MS/MS validation. / Med Chem. 2009 52(2) 329-335. 

In silico approaches to predict drug metabolism are of particular interest to the pharmaceutical industry as having the potential to impact the early drug discovery process as well as in the candidate selection phase. The identification of metabolic soft spots in a new chemical entity could help improve the hepatic... 

The rapid structure identification of metabolites provides an early perspective on the metabolically labile sites or soft spots of a drug candidate [86], This information is useful during lead optimization and can serve to initiate research efforts that deal with metabolism-guided structural modification and toxicity. 

For metabolic stability screens to be most effective, the screens must be tightly linked to some means of gathering information on metabolite structure. Methods for rapidly determining metabolite molecular weight and limited structural information have improved dramatically and allow this approach to be routinely employed (Anari and Baillie, 2005 Watt et al., 2003). The goal of this type of approach is to allow the identification of metabolic soft spots which can then be altered to produce compounds with improved metabolic stability. The literature of successful structural modification to increase stability has recently been reviewed (Thompson, 2001). 

At the early stage of compound selection and optimization for deciding a clinical candidate, drug metabolism studies are often conducted in vitro with liver fractions and in vivo with rats using nonlabeled compounds to define metabolic stability, soft-spot identification, CYP inhibition/induction potential, bioactivation or toxic metabolite formation, major in vitro metabolic pathways, and the limited in vitro interspecies comparison. Mass balance (or ADME) studies with collection of plasma in animals and humans using a... 

FIGURE 15.5 Work flow of metabolic soft spot determination using EMS-EPI or MIM-EPI EIC, extracted ion chromatography PIF, product ion filter NLF, neutral loss filter. 

EMS—EPI is an also effective method for metabolic soft spot analysis, when analytical sensitivity is not an issue. 

Metabolite quantitation plays an important role in drug discovery and development as the level of metabolites may potentially impact the efficacy and safety of a drug (Baillie et al., 2002 Leclercq et al., 2009 Smith and Obach, 2006). Even for metabolites with no biological activity at the clinical relevant dose, the amount of a specific metabolite formed often reveals a major metabolic pathway that may allow medicinal chemists to block some labile sites on the molecule or soft spots to metabolically stabilize the compound. The recent U.S. Food and Drug Administration (FDA) guidance on Safety Testing of Drug Metabolites further put forward the requirements for... 

Shin YG, Le H, Khojasteh C, Hop CE (2011) Comparison of metabolic soft spot predictions of CYP3A4, CYP2C9 and CYP2D6 substrates using MetaSite and StarDrop. Comb Chem High Throughput Screen 14 811-823... 

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