N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Strategies to eliminate reactive metabolites

Practical approaches to resolving reactive metabolite liabilities in early discovery

“…In vitro covalent binding studies with [ 14 C]-PF-915275 ( 14 C-label on the nitrile group) suggested that non-specific binding to proteins was reduced to near background levels when [ 14 C]-PF-915275 was incubated with subcellular fractions (liver S9 and microsomes) of various species in a mixture containing cofactors for conjugative enzymes (UGTs, SULTs etc.). In vivo covalent binding studies in rats following oral administration of 2 mg/ kg of [ 14 C]-PF-915275 also resulted in insignificant binding to liver protein (50.21 pmol/mg liver protein) (Nair et al, 2013). Furthermore, GSH or N-acetylcysteine conjugates were not detected in the bile and urine in these studies.…”

“…In parallel, efforts were invested to identify a backup that lacked the potential for bioactivation. Based on the proposed mechanism of bioactivation, design efforts led to the synthesis of a hydroxymethyl derivative of PF-915275 that maintained potent 11b-HSD type 1 activity and ADME characteristics similar to the lead compound, but showed negative results in the RM assay (Nair et al, 2013).…”

“…The combined strategy of assessing the competing pathways and the dose was applied to mitigate the risk of RMs in an 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) inhibitor project at Pfizer and advance the lead compound, PF-915275 (Figure 12), into the clinic (Nair et al, 2013;Siu et al, 2009). Despite having favorable pharmacological, ADME and PK properties, including excellent metabolic stability and permeability in in vitro assays, GSH conjugates were detected when PF-915275 was tested in the RM assay, suggesting that it had a potential to form electrophilic intermediates.…”

Detecting reactive drug metabolites for reducing the potential for drug toxicity

“…A final case study comes from studies with the N-(pyridylin-2-yl) sulfonamide-containing compound, PF-915275, a potent inhibitor of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) as potential therapy for type 2 diabetes [94]. Due to the need for an excellent safety profile for treating diabetes, risk--benefit analysis for progression to clinical studies was performed on the compound when a screen for bioactivation showed PF-915275 to form GSH adducts in vitro.…”

Mechanistic Insight on the Mode of Action of Colletoic Acid

“…In humans, 11β-HSD1 expression is increased in acquired central obesity and positively correlates to the accumulation of subcutaneous and intra-abdominal fat, body mass index, and insulin resistance, symptoms associated with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). − The inhibition of intracellular cortisol production by blocking 11β-HSD1 ameliorates the risk factors associated with MetS, T2DM, and fatty liver in preclinical studies . Therefore, several medicinal chemistry campaigns have been launched to identify small heterocycle molecules to selectively inhibit 11β-HSD1. − However, the limited molecular complexity presented by heterocycles and the modest clinical performance have promoted the search for natural product inhibitors with rich structure complexity . Despite the potential therapeutic relevance of this biological target, few natural products have been reported as potent and selective inhibitors of this enzyme ( 3 – 4 , Figure ).…”