Discovery of Novel Bicyclic Pyrazoles as Potent PIP5K1C Inhibitors.

Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) is generated by phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) from phosphatidylinositol 4-phosphate (PI4P). Structurally diverse and selective inhibitors against PIP5Ks are required to further elucidate the therapeutic potential for PIP5K inhibition, although the effects of PIP5K inhibition on various diseases and their symptoms, such as cancer and chronic pain, have been reported. Our medicinal chemistry efforts led to novel and potent PIP5K1C inhibitors. Compounds 30 and 33 not only showed potent activity but also demonstrated low total clearance in mice and high levels of kinase selectivity. These compounds might serve as tools to further elucidate the complex biology and therapeutic potential of PIP5K inhibition.

Discovery of benzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivatives as orally available bromodomain and extra-terminal domain (BET) inhibitors with efficacy in an in vivo psoriatic animal model.

Bromodomain and extra-terminal domain (BET) protein plays an important role in epigenetic regulation, and the regulation of disruption contributes to the pathogenesis of cancer and inflammatory disease. With the goal of discovering novel BET inhibitors, especially BRD4 inhibitors, we designed and synthesized several compounds starting from our previously reported pyrido-benzodiazepinone derivative 4 to enhance BRD4 inhibitory activity while avoiding hERG inhibition. Molecular docking studies and structure-activity relationship studies led to the identification of 9-fluorobenzo[f]pyrido[4,3-b][1,4]oxazepin-10-one derivative 43, which exhibited potent BRD4 inhibitory activity with excellent potency in imiquimod-induced psoriasis model mice.

Discovery of novel pyrazolo[1,5-a]pyridine-based EP1 receptor antagonists by scaffold hopping: Design, synthesis, and structure-activity relationships.

A scaffold-hopping strategy towards a new pyrazolo[1,5-a]pyridine based core using molecular hybridization of two structurally distinct EP1 antagonists, followed by structure-activity relationship-guided optimization, resulted in the identification of potent EP1 antagonists exemplified by 4c, 4f, and 4j, which were shown to reduce pathological intravesical pressure in rats when administered at 1mg/kg iv.

Identification of novel 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazoles: Lead generation and optimization toward potent and orally active EP1 receptor antagonists.

Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EP1 antagonist. Lead generation studies provided benzo[d]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC50-clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazole derivative, 7r (IC50 1.1nM; LLE 4.7), which showed a good pharmacological effect when administered intraduodenally in a 17-phenyl trinor-PGE2 (17-PTP)-induced overactive bladder model in rats.

Novel pyrazolo[1,5-a]pyridines as orally active EP1 receptor antagonists: Synthesis, structure-activity relationship studies, and biological evaluation.

Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4-6. Structure-activity relationships (SAR) studies of 4-6 were performed, leading to identification of the nanomolar-level EP1 antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats.

Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3ß (GSK-3ß) inhibitors for type 2 diabetics.

The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3ß inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3ß inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2µM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.

Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3ß.

The synthesis, GSK-3ß inhibitory activity, and anti-microbial activity of bicyclic and tricyclic derivatives of the 5,7-diamino-6-fluoro-4-quinolone-3-carboxylic acid scaffold were studied. Kinase selectivity profiling indicated that members of this class were potent and highly selective GSK-3 inhibitors.

Design, synthesis, and structure-activity relationship studies of novel 2,4,6-trisubstituted-5-pyrimidinecarboxylic acids as peroxisome proliferator-activated receptor gamma (PPARgamma) partial agonists with comparable antidiabetic efficacy to rosiglitazone.

A series of novel 2,4,6-trisubstitutedpyrimidine-5-carboxylic acid derivatives were designed and synthesized with the intent of producing a peroxisome proliferator-activated receptor gamma (PPARgamma) partial agonist for antidiabetic agents. A pharmacophore-driven approach of in-house screening identified compound 7, which led to the identification of compound 9 featuring a 2,4,6-trisubstituted pyrimidine-5-carboxylic acid core. Structure-activity relationship studies of 9 resulted in identifying 4,6-bisbenzylthio-2-methylthiopyrimidine-5-carboxylic acid (50) as the most attractive of all the screened compounds. The X-ray cocrystal structure of 50 bound on PPARgamma revealed that the key hydrogen bond interactions, which are not related to the activation function 2 (AF-2) site, are different from those of the full agonist. Compound 50 showed typical PPARgamma partial agonist properties in the PPARgamma-GAL4 functional assay and weaker differentiation of adipocytes in 3T3-L1 cells than observed with rosiglitazone. Furthermore, 50 displayed comparable antidiabetic efficacy with rosiglitazone in db/db mice, although its potency is 10-fold weaker than that of rosiglitazone.

Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues.

Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH(4)/air solution leads to oxidation of the C15'-C20' double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20' alcohol isomer. The yield of coupled products, which exclusively possess the natural C16' stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20' alcohols is >60%. Preliminary studies of Fe(III)-NaBH(4)/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identify alternatives to O(2) trap at the oxidized carbon, provide a unique entry into C20' functionalized vinblastines, and afford initial insights into the observed C20' diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Delta(19',20')-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.

Analysis of crucial structural requirements of 2-substituted pyrimido[4,5-b][1,5]oxazocines as NK(1) receptor antagonist by axially chiral derivatives.

This study aimed to identify the crucial structural features of 2-substituted 8-methylpyrimido[4,5-b][1,5]oxazocine derivatives. Axially chiral 8-methylpyrimido[4,5-b][1,5]oxazocines bearing a substituent at the C-2 position were synthesized and evaluated as NK(1) antagonists. The results revealed that (aR, 8S)-stereochemistry and the substituent at the C-2 position are important for NK(1) receptor recognition.

Design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-ones as NK1 antagonists.

A series of novel bicyclic pyrimidine derivatives was prepared as part of a search for NK1 antagonist aimed at the treatment of urinary incontinence. Among them, 3g, a pyrimido[4,5-b][1,5]oxazocine derivative, bearing a 4-acetylpiperazinyl group and a 2-methylphenyl group, was shown to have potent NK1 antagonist activity with a K(B) value of 0.105 nM and markedly increased the effective bladder capacity of guinea pigs (59.4% at 0.3 mg/kg iv and 62.8% at 3 mg/kg id). Furthermore, the effect of 3g on bladder function appeared to differ from that of tolterodine, another classical anti-pollakiuria agent, as determined by the distention-induced rhythmic bladder contraction assay using a urethane-anesthetized guinea pig model. Compound 3g is expected to be a promising agent for the treatment of urinary incontinence.

Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones as NK(1) antagonists.

Novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones were designed and prepared as part of a search for NK1 antagonists. Structure-activity relationship studies indicated that the conformational restriction resulting from the incorporation of an oxazocine ring and the presence of a terminal heteroatom on the cyclic amino group at the C-9 position play important roles in NK1, receptor recognition.

2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one as a structurally new NK1 antagonist.

The structurally novel pyrimido[4,5-b][1,5]oxazocine derivative 3, a hybrid compound of pyrido[4,3-b]- and [2,3-b]-1,5-oxazocine (1 and 2, respectively), was designed and synthesized. We examined the atropisomeric property and the NK1 antagonist activity of 3. Compound 3 was found to possess both a feature of 1, free rotation about the biaryl bond, and a feature of 2, potent in vivo activity.