Initial efforts focused on replacing the quinoline moiety employing polymer-assisted solution-phase chemistry. in the central nervous system. There has been considerable effort by both academic and industrial laboratories to develop potent and selective H3 receptor PRKAA2 antagonists for the potential treatment of attention-deficit hyperactivity disorder, dementias, Atractylenolide III schizophrenia, as well as obesity and sleep disorders resulting in a refined H3 antagonist pharmacophore model containing two basic nitrogens separated by a spacer and a central core that also carries a polar group and a lipophilic residue (Figure 2). After having completed its total synthesis, Kennedy and co-workers recognized that the marine alkaloid dispyrin 14 perfectly maps onto this pharmacophore model.136 Dispyrin 14 indeed displayed some H3 antagonist activity (IC50 = 2.35 M) and was used as the starting point for a natural product guided iterative parallel synthesis campaign. Starting from 3-bromo-4-methoxyphenylethylamine 15 five heterocyclic carboxylic acids R1 were coupled using DIC, HOBt and DIEA in DCM. The methyl ether was removed with BBr3 and the resulting phenols alkylated with five R2-aminoalkyl chlorides under microwave irradiation conditions generating 25 different compounds 16. All the compounds showed activity against H3 with more potent compounds containing an ethyl pyrrolidinyl residue in the R2 position (or position of the phenyl ring. Compound 42 was tested in a non-human primate model of hyperglucagonaemia and hyperglycaemia. It dose-dependently decreased glucagon stimulated glycaemia and abolished the Atractylenolide III hyperglycemic effect of exogenously administered glucagon completely at i.v. doses of 1 1 and 3 mg/kg. Compound 42 also showed high plasma exposure and a long plasma half-life in monkeys. This library approach demonstrated that the urea linkage in previously reported hGluR antagonists can be successfully replaced by a number of different thiazole cores and established SARs for binding, selectivity and PK properties for this novel chemical class. Open in a separate window Figure 3 Glucogon receptor antagonists.179 Purinergic P2Y12 receptor antagonists.221 Plavix? (clopidogrel, 43) is an antiplatelet agent approved for stroke and myocardial infarction in patients with atherosclerosis. Its mechanism of action is thought to proceed via metabolism to acid 44 followed by irreversible inactivation of P2Y12, a platelet specific GPCR (Figure 4). This in turn leads to a reduction in adenosine diphosphate (ADP)-stimulated platelet aggregation and the formation of platelet aggregates thereby providing therapeutic benefit. Because 43 is a prodrug requiring metabolic activation, it cannot be used effectively in patients that require emergency treatment Atractylenolide III (delayed time of action) or in patients who cannot metabolize 43. Recognizing the shortcomings of 43, Parlow and colleagues sought to find a new class of P2Y12 receptor antagonists having direct action on the receptor.221 P2Y12-based quinoline antagonists were previously reported by Berlex and this class was used as a starting point for library design and SAR exploration. Initial efforts focused on replacing the quinoline moiety employing polymer-assisted solution-phase chemistry. Piperazine derivatives 46 were coupled with heteroaromatic carboxylic acids 47 in the presence of resin-bound carbodiimide and HOBt. Excess reactants were sequestered with resin-bound isocyanate and a resin-bound secondary amine providing clean intermediates that, post TFA treatment, afforded desired carboxylic-acid-containing analogs 48. Hundreds of compounds were prepared using this approach. The library was evaluated in a human-derived P2Y12 receptor binding Atractylenolide III assay, screening for % inhibition at 10 M. profile, oral bioavailability, and some 340-fold more selective for the P2Y12 receptor versus its closest homolog, the P2Y13 receptor. Heat shock protein 90 (Hsp90) Inhibitors.41 Hsp90 has gained attention in the pharmaceutical industry due to its participation in multiple cell signaling pathways in cancer cells (e.g., PI3K/Akt). Hsp90 is an ATPase protein that acts as a chaperone, binding to multiple oncology relevant client proteins (e.g., Her2, cKit, MET), stabilizing these proteins so to permit their cell signaling function. Inhibition of Hsp90 prevents the necessary folding required to bind and stabilize client proteins. This results in the degradation of the client proteins via the ubiquitin proteasome pathway making Hsp90 an attractive oncology target. Geldanamycin and close synthetic analog 17-allylamino-17-demethoxygeldanamycin (17-AAG) bind to the ATP active site in the clearance. Cho-Schultz and colleagues focused their attention on compound 78, an amide-containing polyphenol and ATP binding site-directed inhibitor of Hsp90 (Figure 5).41 A two-stage solution-phase strategy was devised to explore the.