108297-01-4

Upstream product

• 1126-09-6 4-carbethoxypiperidine 
• 100-44-7 benzyl chloride 
• 24228-40-8 N-benzyl isonipecotic acid ethyl ester 
• 10315-07-8 N-benzylpiperidine-4-carboxylic acid 

Downstream Products

• 195503-44-7 1-benzyl-N-methyl-N-phenylpiperidine-4-carboxamide 
• 609780-46-3 N-[4-(aminocarbonyl)phenyl]-1-benzylpiperidine-4-carboxamide 
• 1190747-06-8 C₂₅H₃₃N₃O₃ 
• 609780-49-6 N-[4-(aminocarbonyl)phenyl]-piperidine-4-carboxamide 
• 1415992-31-2 2-(1-benzylpiperidin-4-yl)-5-bromobenzo[d]oxazole 
• 195503-48-1 (6-Benzyl-1,6-diaza-spiro[2.5]oct-1-en-2-yl)-methyl-phenyl-amine 

Relevant academic research and scientific papers

GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes

GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp-43 with an IC50 value of 0.63 μM by a structure-activity relationship (SAR) study. Further studies showed that Comp-43 reduces mHTT levels by targeting GPR52 and promotes survival of mouse primary striatal neurons. Moreover, in vivo study showed that Comp-43 not only reduces mHTT levels but also rescues HD-related phenotypes in HdhQ140 mice. Taken together, our study confirms that inhibition of GPR52 is a promising strategy for HD therapy, and the GPR52 antagonist Comp-43 might serve as a lead compound for further investigation.

Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction

Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.

4,5-dimethoxy-2-nitrobenzohydrazides and 1-(1-benzylpiperidin-4-yl)ethan-1-ones as potential antioxidant/cholinergic endowed small molecule leads

The objective of this research is to generate leads for developing our ultimate poly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active molecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling (via cholinesterase inhibition) are still being sought for combating Alzheimer’s disease (AD). We differentiate “poly-active” agents from “multi-target” ones by defining them as single molecular entities designed to target only specific contributory synergistic pharmacologies in a disease. For instance, in AD, free radicals either initiate or act in synergy with other pharmacologies, leading to disease worsening. For this preliminary report, a total of 14 (i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives were synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and inhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives (4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance capacity (ORAC) assay. The antioxidant values were either comparable or more potent than the comparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c) yielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base search confirmed that most of the compounds reported herein are new, except 9a and 9c which are also commercially available.

PIPERIDINES AS MENIN INHIBITORS

The present disclosure provides compounds represented by Formula (I): (Formula(I)) and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R2, R3a, R3b, A, G, X, and Y are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I) for use to treat a condition or disorder responsive to menin inhibition such as cancer.

NOVEL COMPOUNDS AS MODULATORS OF GPR-119

The present invention relates to novel compounds of formula (A) and (B) as modulators of GPR-119, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of GPR-119 mediated diseases

2,4-Diamino-quinazolines as inhibitors of β-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer

The synthesis and SAR of a series of 2,4-diamino-quinazoline derivatives as β-catenin/Tcf-4 inhibitors are described. This series was developed by modifying the initial lead 1, which was identified by screening of our compound library and found to inhibit

BENZAMIDE DERIVATIVES

A compound represented by formula (1): wherein X is a single bond or a substituted or unsubstituted lower alkylene group; Z is a saturated or unsaturated monocyclic hydrocarbon ring group or the like; and each of R1, R2, R3 and R4, which may be the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug has inhibitory effect on Rho kinase and hence is useful for treating diseases which are such that morbidity due to them is expected to be improved by inhibition of Rho kinase and secondary effects such as inhibition of the Na+/H+ exchange transport system caused by the Rho kinase inhibition, for example, hypertension.

Benzyl-piperidine derivatives

Benzly-piperidine derivatives of formula I and their pharmaceutically acceptable salts are used in the control of psychotic disorders which are caused by damage to the dopamine system, especially schizophrenia. STR1 A is STR2 B is STR3 R 1, R 2 and R 3 are independently hydrogen, amino, nitro, halogen, lower-alkly or lower-alkoxy. R 4, R 5 and R 6 are independently hydrogen, nitro, halogen, lower-alkyl, lower-alkoxy, cyano, trifluoromethyl, amino, lower-alkylamino or di-lower-alkylamino. R 7, R 2 and R 9 are independently hydrogen, amino or nitro.

112. Novel heterospirocyclic 3-amino-2H-azirines as synthons for heterocyclic α-amino acids)

The heterospirocyclic N-methyl-N-phenyl-2H-azirin-3-amines (3-(N- methyl-N-phenylamino)-2H-azirines) 1a-d with a tetrahydro-2H-pyran, tetrahydro-2H-thiopyran, and a N-protected piperidine ring respectively, were synthesized from the corresponding heterocyclic 4-carboxamides 2 by consecutive treatment with lithium diisopropylamide (LDA), diphenyl phosphorochloridate (DPPCl), and sodium azide (Scheme 4). The reaction of these aminoazirines with thiobenzoic acid in CH2Cl2 at room temperature gave the thiocarbamoyl-substituted benzamides 13a-d in high yield. The azirines 1a-d were used as synthons for heterocyclic α-amino acids in the preparation of tripeptides of the type Z-Aib-Xaa-Aib-N(Ph)Me (18) by following the protocol of the 'azirine/ox-azolone method': treatment of Z- Aib with 1 to give the dipeptide amide 15, followed by selective hydrolysis to the corresponding acid 16 and coupling with the 2,2-dimethyl-2H-azirin-3- amine 17 gave 18, again in high yield (Scheme 5). With some selected examples of 18, the selective deprotection of the amino and the carboxy group, respectively, was demonstrated (Scheme 6). The solid-state conformations of the protected tripeptides 18a-d, as well as that of the corresponding carbocyclic analogue 18e, were determined by X-ray crystallography (Figs. 1- 3 and Tables 1-3). All five tripeprides adopt a β-turn conformation of type III or III. The solvent dependence of the chemical shifts of the NH resonances (Fig. 6) suggests that there is an intramolecular H-bond between H-N(4) and O(11) in all cases, which is an indication that a relatively rigid β-turn structure also persists in solution. Surprisingly, the tripeptide acid 20a shows no intramolecular H-bond in the crystalline state (Fig. 7); O(11) is involved in an intermolecular H-bond with the OH group of the carboxy function.