Structure−Activity Relationships of 1-Alkyl-5-(3,4-dichlorophenyl)- 5-{2-[(3-substituted)-1-azetidinyl]ethyl}-2-piperidones. 1. Selective Antagonists of the Neurokinin-2 Receptor

Abstract

The design, synthesis, and pharmacological evaluation of a novel class of neurokinin-2 (NK2) antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-[2-[(3-substituted)-1-azetidinyl]ethyl]-2-piperidones (5-44) are described. These compounds are formally derived from 2 by incorporating the metabolically vulnerable N-methylamide function into a more stable six-membered ring lactam 4, resulting in increased stability in human liver microsome (HLM) preparations relative to 2 (T1/2(HLM) of 30 min vs <10 min for 2). This series was further optimized by replacing the 4,4-disubstituted piperidine functionality found in 4 with simple 3-substituted azetidines. This series, exemplified by 1-benzyl-5-(3,4-dichlorophenyl)-5-[2-[3-(4-morpholinyl)-1-azetidinyl]ethyl]-2-piperidone 5, was found to possess excellent functional potency for the NK2 receptor in the Rabbit pulmonary artery (RPA) assay (pA2 = 9.3) and increased in vitro metabolic stability (T1/2(HLM) = 70 min) relative to 4. Metabolic route identification studies revealed that N-benzyl oxidation was a major route in this relatively lipophilic lead (log D = 3.2). Further exploration of the N-lactam substituent SAR targeting reduced lipophilicity to attenuate P-450 metabolism revealed that incorporation of a cyclopropylmethyl group in this region of the molecule gave a balance of good potency and high metabolic stability. For example, the significantly less lipophilic analogue 29 (log D = 2.3) possessed both good functional potency (RPA, pA2 = 8.1) and high in vitro metabolic stability (T1/2(HLM) = 120 min). Optimization in this N-cyclopropylmethyllactam series by modification of the nature of the azetidine 3-substituent as a strategy to further increase potency and moderate log D led to the identification of sulfamide analogue 33, which possessed both excellent metabolic stability in vitro (T1/2(HLM) >120 min) and high potency in both RPA (pA2 = 8.9) and human bladder smooth muscle (pK(b) = 8.9) functional assays. In addition, NK2 antagonist 33 (IC50 = 4 nM) showed excellent selectivity over both the related human neurokinin receptors h-NK1 (IC50 = 7.9 microM) and h-NK3 (IC50 = 1.8 microM) in radioligand binding studies.

Murine Efficacy and Pharmacokinetic Evaluation of the Flaviviral NS5 Capping Enzyme 2-Thioxothiazolidin-4-One Inhibitor BG-323

“…This is likely due to the biotransformation of BG-323 as the small molecule is modified or degraded by metabolic enzymes. Strategies to circumvent metabolic destabilization of drug-like compounds include blocking the active metabolic site(s) in the small molecule by replacing a highly reactive group with a less reactive group [27,28], adding a bulky group that increases steric hindrance proximal to the reactive group [29], incorporating the labile group into a ring structure [30] or removing the labile group from the small molecule altogether [31]. Such alterations can lead to a several fold increase in the stability of a small molecule and can significantly increase the half-life of the compound.…”

“…Other successful strategies for increasing metabolic stability rely on the specificity of metabolic enzymes for their substrates. Changing chirality [32], reducing lipophilicity [33] and changing the size of cyclized groups within the molecule [30] have also been shown to have a favorable effect on small molecule stability. The application of one or more of these strategies to BG-323 could stabilize the compound sufficiently to increase the half-life and potentially increase the ability of the BG-323 to inhibit viral replication in vivo .…”

G-Coupled Protein Receptors and Breast Cancer Progression: Potential Drug Targets

“…The NK2 receptor antagonist, SR-48, 968 and other classes were identified by random library screen and modification of compounds [43]. In other cases, a different class of stable NK2 antagonists were obtained by incorporating the Nmethylamide into six-membered ring lactam 4 ring [44]. Since NK2 receptors are mostly distributed throughout the periphery, as opposed to the central nervous system, in the case of NK1 [34]; Selective nonpeptide antagonists of NK2 raised interest as potential therapies for urinary incontinence, bowel, and airway disorders [45].…”

An Automated High-Throughput Metabolic Stability Assay Using an Integrated High-Resolution Accurate Mass Method and Automated Data Analysis Software

“…These assays use microsomes, S9, and cytosol fractions from various species and have been extended to stability assessment in living hepatocytes (Obach et al, 1997;Niro et al, 2003;Ito and Houston, 2004). These assays are regularly used by pharmaceutical companies to provide valuable insights for drug design during discovery research to optimize pharmacokinetic profiles of chemical series (MacKenzie et al, 2002;Korfmacher, 2003;Nassar et al, 2004). In silico tools for the prediction of metabolic stability have been developed using various matrices, with number of compounds ranging from a handful few up to thousands (Bursi et al, 2001;Shen et al, 2003;Sakiyama et al, 2008).…”