Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors

Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound <b>1</b>, a novel series of dihydrooxadiazoles was discovered. Additional structure–activity relationship (SAR) study of this series led to the identification of compound <b>38</b> as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed

Development of Novel Benzomorpholine Class of Diacylglycerol Acyltransferase I Inhibitors

Diacylglycerol acyltransferase 1 (DGAT1) presents itself as a potential therapeutic target for obesity and diabetes for its important role in triglyceride biosynthesis. Herein we report the rational design of a novel class of DGAT1 inhibitors featuring a benzomorpholine core (<b>23n</b>). SAR exploration yielded compounds with good potency and selectivity as well as reasonable physical and pharmacokinetic properties. This class of DGAT1 inhibitors was tested in rodent models to evaluate DGAT1 inhibition as a novel approach for the treatment of metabolic diseases. Compound <b>23n</b> conferred weight loss and a reduction in liver triglycerides when dosed chronically in mice with diet-induced obesity and depleted serum triglycerides following a lipid challenge

Synthesis and SAR Studies of Fused Oxadiazines as γ‑Secretase Modulators for Treatment of Alzheimer's Disease

Fused oxadiazines (<b>3</b>) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure–activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds <b>8r</b> and <b>8s</b> that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound <b>8s</b> confirm that the oxadiazine series of compounds are potent GSMs

Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (<b>33</b>) with an EC₅₀ of 2 nM in the hu-GPR109a assay. Compound <b>33</b> demonstrated good oral bioavailability in all species. Compound <b>33</b> exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound <b>33</b> had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound <b>33</b> was evaluated in human clinical trials

Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma

A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl­((3<i>aS</i>,9<i>R</i>,9<i>aR</i>)-7-fluoro-4-(4-(trifluoromethoxy)­benzoyl)-2,3,3<i>a</i>,4,9,9<i>a</i>-hexahydro-1<i>H</i>-cyclopenta­[<i>b</i>]­quinolin-9-yl)­amino)-4-oxobutanoic acid (<b>15c</b>, <b>MK-8318</b>) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma