191090-84-3

Upstream product

• 1124-33-0 4-nitraminopyridine N-oxide 
• 1121-76-2 4-chloropyridine N-oxide 
• 873-76-7 para-Chlorobenzyl alcohol 
• 35421-08-0 4-hydroxybenzyl chloride 
• 626-03-9 3-deazauracil 
• 622-95-7 4-chlorobenzyl bromide 
• 153034-86-7 2-chloro-4-iodopyridine 
• 1260494-65-2 2-chloro-4-(4-chlorobenzyloxy)pyridine 
• 924311-88-6 4-[(4-chlorobenzyl)oxy]pyridine 1-oxide 

Downstream Products

• 1260492-65-6 4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride 
• 1260494-72-1 tert-butyl 8-(4-(4-chlorobenzyloxy)-2-oxopyridin-1 (2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4, 3-b]indole-2 (1H)-carboxylate 
• 1447910-81-7 4-((4-chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 
• 1447913-77-0 4-((4-chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyrimidin-6-yl)pyridin-2(1H)-one 
• 1447911-27-4 4-((4-chlorobenzyl)oxy)-1-(2-cyclopropyl-1-propyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one 
• 1447913-88-3 4-((4-chlorobenzyl)oxy)-1-(1-methyl-2-propanoyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one 
• 1447913-74-7 4-((4-chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo[1,2-b]pyridazin-6-yl)pyridin-2(1H)-one 

Relevant academic research and scientific papers

hERG Optimization of Benzofuro?Pyridine and Pyrazino?Indole Derivatives as MCHR1 Antagonists

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro?pyridine and pyrazino?indole scaffold was performed. We confirmed that fine-tuning lipophilicity and basic pKa by modifying the benzyl group and introducing different substituents on the aliphatic nitrogen sidechain decreases both hERG inhibition and metabolic clearance. We have succeeded to develop excellent in vitro parameters in the case of compounds 17 (4-[(5-chloropyridin-2-yl)methoxy]-1-[4-(2-hydroxyethyl)-8-oxa-4-azatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraen-11-yl]-1,2-dihydropyridin-2-one monohydrochloride) and 23 g (4-[(5-chloropyridin-2-yl)methoxy]-1-(1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)pyridin-2(1H)-one monohydrochloride), which can be considered as valuable tools for further pharmacological investigation.

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition

Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q-u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats.

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pKa 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test

To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50 = 35 nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9- condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile.

1-(DIHYDRONAPHTHALENYL)PYRIDONES AS MELANIN-CONCENTRATING HORMONE RECEPTOR 1 ANTAGONISTS

This invention relates to novel 1-(dihydronaphthalenyl)pyridones which are antagonists of the melanin-concentrating hormone receptor 1 (MCHR1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy

AZINONE-SUBSTITUTED AZEPINO[b]INDOLE AND PYRIDO-PYRROLO-AZEPINE MCH-1 ANTAGONISTS, METHODS OF MAKING, AND USE THEREOF

Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are als

(1-AZINONE) -SUBSTITUTED PYRIDOINDOLES AS MCH ANTAGONISTS

Substituted pyridoindoles for incorporation in pharmaceutical compositions employed in the treatment of various diseases correspond to formula (I) wherein R1 is H or optionally substituted alkyl; R2, R3, R4 are

PYRIDONE AND PYRIDAZINONE DERIVATIVES AS MCH ANTAGONISTS

The present invention relates to pyridone and pyridazinone derivatives as listed in claim 1 including their salts. Moreover the invention relates to pharmaceutical compositions containing at least one compound according to the invention. By virtue of thei

INDOLE DERIVATIVES

The present invention relates to indole derivatives which bind to the MCHl receptor. In separate aspects, the subject invention is directed to uses of said compounds in the preparation of a pharmaceutical composition for the treatment of obesity and CNS related disorders and to methods of treating said disorders comprising administering a therapeutically effective amount of a compound of the invention.

Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase

The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-