871507-15-2

Upstream product

• 99-76-3 methyl 4-hydroxylbenzoate 
• 134138-88-8 4-(quinolin-2-ylmethyloxy)benzoyl chloride 
• 137426-86-9 4-(2-Quinolinylmethoxy)benzoic acid methyl ester 
• 123724-16-3 4-(quinolin-2-ylmethyloxy)benzoic acid 
• 4377-41-7 2-Chloromethylquinoline 
• 108-89-4 picoline 
• 871507-14-1 N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide 

Downstream Products

• 898562-94-2 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline 
• 898562-93-1 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline 
• 871507-11-8 2-((4-(4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline 
• 871507-16-3 3-(dimethylamino)-2-(pyridin-4-yl)-1-(4-(quinolin-2-ylmethoxy)phenyl)prop-2-en-1-one 

Relevant academic research and scientific papers

Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain

2-((4-(1-[11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [11C]CH3I, ～45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [11C]MP-10 as a PDE10A PET tracer.

Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3- yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia

By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.

Heteroaromatic quinoline compounds

The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. In particular, the invention relates to said compounds which are selective inhibitors of PDE10. The invention also relates to intermediates for preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of said compounds in a method for treating certain central nervous system (CNS) or other disorders.

PHOSPHODIESTERASE 10 INHIBITION AS TREATMENT FOR OBESITY-RELATED AND METABOLIC SYNDROME-RELATED CONDITIONS

The present invention provides methods to decrease body weight and/or body fat in animals, e.g., in the treatment of overweight or obese patients (e.g., humans or companion animals), or as a means to produce leaner meat in food stock animals (e.g., cattle, chickens, pigs), methods to treat non-insulin dependent diabetes (NIDDM), metabolic syndrome, or glucose intolerance, in patients in need thereof by administering a PDE10 inhibitor (alone or in combination with another therapeutic agent), kits for the above-identified therapeutic uses, and methods of identifying PDE10 inhibitors for the above-described therapeutic uses.