Additional file 1: of Augmentation effect of acupuncture on Bi’nao for hypophasis in patients with Bell’s palsy: study protocol for a randomized controlled trial

A complete SPIRIT checklist. (DOC 122 kb

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