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

被引：61

作者：

Griffith, David A. ^{[1
]}

Hadcock, John R.

Black, Shawn C.

Iredale, Philip A.

Carpino, Philip A.

DaSilva-Jardine, Paul

Day, Robert

DiBrino, Joseph

Dow, Robert L.

Landis, Margaret S.

O'Connor, Rebecca E.

Scott, Dennis O.

机构：

[1] Pfizer Global Res & Dev, Dept Cardiovasc Metab & Endocrine Dis, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 02期

关键词：

CENTRAL-NERVOUS-SYSTEM; P-GLYCOPROTEIN EFFLUX; IN-VITRO; ENDOCANNABINOID SYSTEM; INVERSE AGONIST; BODY-WEIGHT; FOOD-INTAKE; BLOOD; SR141716A; LIPOPHILICITY;

D O I：

10.1021/jm8012932

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (K-i = 0.7 nM) and functional assays (K-i = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.

引用

页码：234 / 237

页数：4

共 38 条

[1] In vitro P-glycoprotein affinity for atypical and conventional antipsychotics [J].

Boulton, DW ;

DeVane, CL ;

Liston, HL ;

Markowitz, JS .

LIFE SCIENCES, 2002, 71 (02) :163-169

[2] New bicyclic cannabinoid receptor-1 (CB1-R) antagonists [J].

Carpino, PA ;

Griffith, DA ;

Sakya, S ;

Dow, RL ;

Black, SC ;

Hadcock, JR ;

Iredale, PA ;

Scott, DO ;

Fichtner, MW ;

Rose, CR ;

Day, R ;

Dibrino, J ;

Butler, M ;

DeBartolo, DB ;

Dutcher, D ;

Gautreau, D ;

Lizano, JS ;

O'Connor, RE ;

Sands, MA ;

Kelly-Sullivan, D ;

Ward, KM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (03) :731-736

[3] Synthesis, corticotropin-releasing factor receptor binding affinity, and pharmacokinetic properties of triazolo-, imidazo-, and pyrrolopyrimidines and -pyridines [J].

Chorvat, RJ ;

Bakthavatchalam, R ;

Beck, JP ;

Gilligan, PJ ;

Wilde, RG ;

Cocuzza, AJ ;

Hobbs, FW ;

Cheeseman, RS ;

Curry, M ;

Rescinito, JP ;

Krenitsky, P ;

Chidester, D ;

Yarem, JA ;

Klaczkiewicz, JD ;

Hodge, CN ;

Aldrich, PE ;

Wasserman, ZR ;

Fernandez, CH ;

Zaczek, R ;

Fitzgerald, LW ;

Huang, SM ;

Shen, HL ;

Wong, YN ;

Chien, BM ;

Quon, CY ;

Arvanitis, A .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (05) :833-848

[4] The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: Evaluation using the MDR1A/1B knockout mouse model [J].

Doran, A ;

Obach, RS ;

Smith, BJ ;

Hosea, NA ;

Becker, S ;

Callegari, E ;

Chen, CP ;

Chen, X ;

Choo, E ;

Cianfrogna, J ;

Cox, LM ;

Gibbs, JP ;

Gibbs, MA ;

Hatch, H ;

Hop, CECA ;

Kasman, IN ;

LaPerle, J ;

Liu, JH ;

Liu, XR ;

Logman, M ;

Maclin, D ;

Nedza, FM ;

Nelson, F ;

Olson, E ;

Rahematpura, S ;

Raunig, D ;

Rogers, S ;

Schmidt, K ;

Spracklin, DK ;

Szewc, M ;

Troutman, M ;

Tseng, E ;

Tu, MH ;

Van Deusen, JW ;

Venkatakrishnan, K ;

Walens, G ;

Wang, EQ ;

Wong, D ;

Yasgar, AS ;

Zhang, CH .

DRUG METABOLISM AND DISPOSITION, 2005, 33 (01) :165-174

[5] Activation of the peripheral endocannabinoid system in human obesity [J].

Engeli, S ;

Böhnke, J ;

Feldpausch, M ;

Gorzelniak, K ;

Janke, J ;

Bátkai, S ;

Pacher, P ;

Harvey-White, J ;

Luft, FC ;

Sharma, AM ;

Jordan, J .

DIABETES, 2005, 54 (10) :2838-2843

[6] Assessment of blood-brain barrier penetration:: In silico, in vitro and in vivo [J].

Feng, MR .

CURRENT DRUG METABOLISM, 2002, 3 (06) :647-657

[7] Generation of a set of simple, interpretable ADMET rules of thumb [J].

Gleeson, M. Paul .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (04) :817-834

[8]

HADCOCK JR, 2008, CLIN PHARM THER, V83, pS78

[9] Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice [J].

Hao, SZ ;

Avraham, Y ;

Mechoulam, R ;

Berry, EM .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2000, 392 (03) :147-156

[10] Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice [J].

Hildebrandt, AL ;

Kelly-Sullivan, DM ;

Black, SC .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2003, 462 (1-3) :125-132

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