Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists

Abstract Image

We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0–t = 359 ng·h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC–MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0–t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug25b showed good efficacy in selected rodent models of psychosis.


Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists

Medicinal Chemistry Division, Pharmacology Division, and §Drug Metabolism and Pharmacokinetics,Glenmark Research Centre, A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India
J. Med. Chem., 2015, 58 (20), pp 8292–8308
DOI: 10.1021/acs.jmedchem.5b01240
Publication Date (Web): September 30, 2015
*Phone: +91-226772-0000. Fax: +91-2222-2778-2525. E-mail:

A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines

A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines


  • Medicinal Chemistry Division, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai 400709, India

A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines


A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently syn-thesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)ac-rylamides and selected b-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated conjugate addition of a b-keto ester to 2-cyano-3,3-bis(methylthio)acrylamide followed by loss of methyl mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group. The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3-(methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-dihydropyridine

Corresponding author. Tel.: þ91 22 6772 0000; fax: þ91 22 2778 1206; e-mail address: (A. Thomas).


4.2. Synthesis of carbamoyl ketene dithioacetals (1aem); general procedure23 The carbamoyl ketene dithioacetals were prepared by reported procedure by the reaction of 2-cyanoacetamides (100 mmol) with carbon disulfide (7.22 mL, 120 mmol) in the presence of excess potassium fluoride (116 g, 2000 mmol) in dry DMF (150 mL)followed by alkylation of the intermediate potassium dithiolate with methyl iodide (13.70 mL, 220 mmol) in a one-pot reaction. The spectral and analytical data of known carbamoyl ketene dithioacetals 1a, 22 1b, 29 1d, 30 1e, 31 1g, 15b 1h, 32 1i, 15b 1j15b were in agreement with those reported in the literature.


In summary, we have developed a versatile synthetic method for the preparation of a variety of poly-functional N-alkyl and Naryl 6-oxo-1,6-dihydropyridines using appropriate 2-cyano-3,3- bis(methylthio)acrylamides and a b-keto ester in a single-step using potassium hydrogen carbonate as the base in boiling acetone. The method developed has potential applications for assembling a variety of structurally diverse functionalized pyridones from readily available starting materials. The use of inexpensive starting materials, mild reaction conditions, relatively short reaction time, a straightforward purification process and good yields of products are the main attractions of the method. The present method for the synthesis of dihydropyridones with two points of structural diversity and bearing three functional groups for additional structural modification represents superiority over existing methods and holds enormous potential in synthetic and medicinal chemistry.


New Drug Approvals



For treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.


(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(Acetyloxy)-15-{[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[,10.04,7]heptadec-13-ene-2-yl benzoate


Jevtana, Taxoid XRP6258, Cabazitaxelum, 183133-96-2, Xrp6258, CHEBI:63584, XRP-6258, TXD 258, XRP 6258
Molecular Formula: C45H57NO14   Molecular Weight: 835.93238

EMA:LinkUS FDA:link

Cabazitaxel is prepared by semi-synthesis from 10-deacetylbaccatin III (10-DAB) which is extracted from yew tree needles. The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxy-tax-11-en-2-yl benzoate and is marketed as a 1:1 acetone solvate (propan-2-one),

Cabazitaxel is an anti-neoplastic used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has progressed despite treatment with docetaxel. Cabazitaxel is prepared by semi-synthesis with a precursor extracted from yew needles (10-deacetylbaccatin III). It was approved…

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How to Handle Drug Polymorphs… Case Study of Trelagliptin Succinate

New Drug Approvals

Pharmaceutical API Polymorphs… case study of Trelagliptin
CASE STUDY WITH..Compound I having the formula
Figure imgf000073_0001
Active pharmaceutical ingredients (APIs), frequently delivered to the patient in the solid-state as part of an approved dosage form, can exist in such diverse solid forms as polymorphs, pseudopolymorphs, salts, co-crystals and amorphous solids. Various solid forms often display different mechanical, thermal, physical and chemical properties that can remarkably influence the bioavailability, hygroscopicity, stability and other performance characteristics of the drug.
Hence, a thorough understanding of the relationship between the particular solid form of an active pharmaceutical ingredient (API) and its functional properties is important in selecting the most suitable form of the API for development into a drug product. In past decades, there have been significant efforts on the discovery, selection and control…

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CHINESE MEDICINE-Xuezhikang , A blood lipid regulator

New Drug Approvals


Xuezhikang, the extract of red yeast rice, has been widely used as a Chinese traditional medicine for the therapy of patients with cardiovascular diseases. It contains natural Lovastatin and its homologues, as well as unsaturated fatty acids, flavonoids, plant sterols and other biologically active substances

The product is a world-recognized blood lipid regulator, which is made by extracting from “specially-made red yeast rice”. It combines modern high-tech biotechnology with traditional Chinese medicine, which can safely and effectively regulate blood lipids in a comprehensive way with proven curative effects and reliable safety.

Pharmacological Effects: the product can reduce blood cholesterol, triglycerides, low density lipoprotein cholesterol, improve high density lipoprotein cholesterol, inhibit atherosclerotic plaque formation, and protect vascular endothelial cells; and inhibit lipid deposition in the liver. The large-scale evidence-based research has proven that long-term use of XUEZHIKANG can greatly reduce the risk of CHD occurrence and decrease the mortality. XUEZHIKANG…

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Zucapsaicin (Zuacta)

New Drug Approvals

Chemical structure of zucapsaicin

Zucapsaicin (Zuacta), cas 25775-90-0

Chemical name: (Z)-8-methyl-N-vanillyl-6-nonenamide
Molecular formula: C18H27NO3
Molecular mass: 305.41

E merck

Civamide, cis-Capsaicin,

Civanex (zucapsaicin) cream is a TRPV-1 modulator in development for the treatment of signs and symptoms of osteoarthritis of the knee.
Zucapsaicin, the cis-isomer of the natural product capsaicin, is a
topical analgesic that was initially developed by Winston Pharmaceuticals
and approved in Canada in July 2010 for the treatment of
severe pain in adults with osteoarthritis of the knee.

Bronson, J.; Dhar, M.; Ewing, W.; Lonberg, N. In Annual Reports in MedicinalChemistry; John, E. M., Ed.; Academic Press, 2011; Vol. 46, p 433.

The advantagesof zucapsaicin compared with naturally-occurring capsaicin, are reported to be a lesser degree of local irritation (stinging, burning,

erythema) in patients and a greater degree of efficacy in preclinical
animal models of pain.

Bernstein, J. E. U.S. 5063060, 1991.
Bernstein, J. E. U.S. 20050084520 A1, 2005.

The analgesic action…

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