CP-945598 HCl

CP 945598 hydrochloride is a selective and high affinity CB1 antagonist with Ki value of 0.7 and 0.12 nM for binding and functional assays, respectively [1].
The CB1 receptor is a G protein-coupled cannabinoid receptor located primarily in the central and peripheral nervous system and plays an important role in energy homeostasis.
CP 945598 dose-dependently reversed the four characteristic effects (hypothermia, anti-nociception, hypo-locomotion, and catalepsy) of a centrally acting cannabinoid agonist (CP 55940).
In mice model, CP 945598 (17.8 mg/kg s.c.) increased locomotor activity. In Sprague–
Dawley rats, CP 945598 reduced food intake in a dose and concentration dependent way. With doses of 10 mg/kg and 30 mg/kg, CP 945598 increased energy expenditure by 16% and 19%, respectively. Also, ex vivo brain receptor occupancy increased to 33–36% in a dose-related way. In diet-induced obese mice, CP 945598 significantly decreased body weight by 9% compared to vehicle-treated mice [2].
References:
[1]. Griffith DA, Hadcock JR, Black SC, et al. Discovery of 1-[9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist. J Med Chem, 2009, 52(2): 234-237.
[2]. Hadcock JR1, Griffith DA, Iredale PA, et al. In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB1 receptor antagonist for the management of obesity. Biochem Biophys Res Commun, 2010, 394(2): 366-371.

The risk reduction of recurrent periodontal pathogens of local application minocycline HCl 2% gel, used as an adjunct to scaling and root planing for chronic periodontitis treatment.[Pubmed:28331333]

Ther Clin Risk Manag. 2017 Mar 10;13:307-314.

BACKGROUND: The aim of this study was to evaluate the clinical and microbiological effects of local application minocycline HCl 2% gel, used as an adjunct to scaling and root planing (SRP) for treatment of chronic periodontitis (CP). CP is an inflammation of periodontal tissue that is caused mainly by bacterial infection, where periodontal destruction such as loss of attachment and bone destruction occurred. METHODS: A total of 81 subjects with moderate to severe periodontitis whose baseline clinical attachment loss (CAL) was >/=4 mm were randomly assigned to receive SRP alone (control group, N=39) or SRP followed by four times of local application of minocycline HCl gel (Periocline) once a week (test group, N=42). Pocket depth, CAL, and papilla bleeding index were examined at baseline, 21 days, 2, 3, and 6 months. Subgingival plaque samples were collected with sterile curettes and were analyzed by real-time polymerase chain reaction for the presence of three periodontal pathogens (Porphyromonas gingivalis [P.g.], Tannerella forsythia [T.f.], and Treponema denticola [T.d.]) at baseline, 2, 3, and 6 months. RESULTS: The number of bacteria was reduced in both groups at 2 months after baseline (SRP treatment). The changes (2-6 months) in T.d. and T.f. counts in the test group were significantly lower than those in the control group. In the control group, a significant regrowth of P.g., T.f., and T.d. was observed from 2 to 6 months and of P.g. and T.f. from 3 to 6 months. On the other hand, in the test group, the number of the three bacteria did not significantly increase during the 6-month period. CONCLUSION: The results showed that local application of minocycline, used as an adjunct to SRP, was effective for suppressing regrowth of periodontal pathogens, suggesting its risk reduction of recurrent periodontal pathogens in CP.

Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid alpha-Glucosidase in Pompe Patients Co-administered with Alglucosidase alpha.[Pubmed:28341561]

Mol Ther. 2017 May 3;25(5):1199-1208.

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid alpha-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.

Comparative plasma and tissue distribution of Sun Pharma's generic doxorubicin HCl liposome injection versus Caelyx((R)) (doxorubicin HCl liposome injection) in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats.[Pubmed:28349166]

Cancer Chemother Pharmacol. 2017 May;79(5):899-913.

PURPOSE: The liposomal formulation of doxorubicin [doxorubicin (DXR) hydrochloride (HCl) liposome injection, Caelyx((R))] alters the tissue distribution of DXR as compared with nonliposomal DXR, resulting in an improved benefit-risk profile. We conducted studies in murine models to compare the plasma and tissue distribution of a proposed generic DXR HCl liposome injection developed by Sun Pharmaceuticals Industries Limited (SPIL DXR HCl liposome injection) with Caelyx((R)). METHODS: The plasma and tissue distributions of the SPIL and reference DXR HCl liposome injections were compared in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats. Different batches and different lots of the same batch of the reference product were also compared with each other. RESULTS: The SPIL and reference DXR HCl liposome injections exhibited generally comparable plasma and tissue distribution profiles in both models. While minor differences were observed between the two products in some tissues, different batches and lots of the reference product also showed some differences in the distribution of various analytes in some tissues. The ratios of estimated free to encapsulated DXR for plasma and tissue were generally comparable between the SPIL and reference DXR HCl liposome injections in both models, indicating similar extents of absorption into the tissues and similar rates of drug release from liposomes. CONCLUSIONS: The plasma and tissue distribution profiles of the SPIL and reference DXR HCl liposome injections were shown to be generally comparable. Inconsistencies between the products observed in some tissues were thought to be due to biological variation.

A global coupled cluster potential energy surface for HCl + OH <--> Cl + H2O.[Pubmed:28327711]

Phys Chem Chem Phys. 2017 Apr 12;19(15):9770-9777.

A new and more accurate full-dimensional global potential energy surface (PES) for the ground electronic state of the ClH2O system is developed by fitting 15 777 points obtained using an explicitly correlated unrestricted coupled-cluster method with single, double, and perturbative triple excitations (UCCSD(T)-F12b). The fitting is carried out using the permutation invariant polynomial-neural network (PIP-NN) method and has an error of 6.9 meV. The new PES has a slightly lower barrier for the atmospherically important HCl + OH --> Cl + H2O reaction than the previous PES based on multi-reference configuration interaction (MRCI) calculations. As a result, it should provide a better characterization of the kinetics. Quantum dynamical calculations of reaction probabilities for both the forward and reverse reactions are performed on this new PES and compared with those on the MRCI PES. They reveal notable differences, resulting apparently from subtle differences in the PESs.

In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB(1) receptor antagonist for the management of obesity.[Pubmed:20211605]

Biochem Biophys Res Commun. 2010 Apr 2;394(2):366-71.

Cannabinoid CB(1) receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB(1) receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB(1) receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CB(1) receptors in both binding (K(i)=0.7 nM) and functional assays (K(i)=0.2 nM). The compound has low affinity (K(i)=7600 nM) for human CB(2) receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CB(1) receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CB(1) receptor competitive antagonist that may further our understanding of the endocannabinoid system.

Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4- carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist.[Pubmed:19102698]

J Med Chem. 2009 Jan 22;52(2):234-7.

We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.

Otenabant Hydrochloride is a potent and selective cannabinoid receptor CB1 antagonist with Ki of 0.7 nM, exhibits 10,000-fold greater selectivity against human CB2 receptor.

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