Novel 2-imidazoles as potent, selective and CNS penetrant α1A adrenoceptor partial agonists

被引：19

作者：

Roberts, Lee R. ^{[1
]}

Bryans, Justin ^{[1
]}

Conlon, Kelly ^{[2
]}

McMurray, Gordon ^{[2
]}

Stobie, Alan ^{[1
]}

Whitlock, Gavin A. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Sandwich Labs, Dept Chem, Sandwich CT13 9NJ, Kent, England

[2] Pfizer Global Res & Dev, Dept Genitourinary Biol, Sandwich Labs, Sandwich CT13 9NJ, Kent, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 24期

关键词：

alpha(1A) adrenoceptor; Partial agonist; 2-Imidazole; CNS penetration; Selectivity;

D O I：

10.1016/j.bmcl.2008.10.066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of central nervous system (CNS) penetrant indane 2-imidazoles have been identified as potent, partial agonists of the alpha(1A) adrenergic receptor, having good selectivity over the alpha(1B), alpha(1D) and alpha(2) sub-types. A key structural motif to impart selectivity is a methylene spacer between the indane and a pendant substituent, which includes heterocycles, sulphones and ethers. Introduction of an ortho-halogen to this group led to a lowering of intrinsic efficacy (E-max). (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6437 / 6440

页数：4

共 11 条

[1] HYDROGEN-BONDING .9. SOLUTE PROTON DONOR AND PROTON ACCEPTOR SCALES FOR USE IN DRUG DESIGN [J].

ABRAHAM, MH ;

DUCE, PP ;

PRIOR, DV ;

BARRATT, DG ;

MORRIS, JJ ;

TAYLOR, PJ .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2, 1989, (10) :1355-1375

[2] HYDROGEN-BONDING .10. A SCALE OF SOLUTE HYDROGEN-BOND BASICITY USING LOG K VALUES FOR COMPLEXATION IN TETRACHLOROMETHANE [J].

ABRAHAM, MH ;

GRELLIER, PL ;

PRIOR, DV ;

MORRIS, JJ ;

TAYLOR, PJ .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2, 1990, (04) :521-529

[3]

AONO T, 1978, CHEM PHARM BULL, V26, P1153

[4]

CONLON K, UNPUB

[5] Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs [J].

Doan, KMM ;

Humphreys, JE ;

Webster, LO ;

Wring, SA ;

Shampine, LJ ;

Serabjit-Singh, CJ ;

Adkison, KK ;

Polli, JW .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 303 (03) :1029-1037

[6] Structure-brain exposure relationships [J].

Hitchcock, Stephen A. ;

Pennington, Lewis D. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (26) :7559-7583

[7] Aromatic spiranes .22. Preparation of cyclopenteno-4,5-indan-1-one and 2-carbomethoxy- and 4-chloromethyl-indane as synthones for the syntheses of anellated 2,2'-spirobiindanone [J].

Melmer, M ;

Neudeck, H .

MONATSHEFTE FUR CHEMIE, 1996, 127 (03) :275-290

[8] Predicting properties and tuning physicochemical in lead optimization:: Amine basicities [J].

Morgenthaler, Martin ;

Schweizer, Eliane ;

Hoffmann-Roeder, Ania ;

Benini, Fausta ;

Martin, Rainer E. ;

Jaeschke, Georg ;

Wagner, Bjoern ;

Fischer, Holger ;

Bendels, Stefanie ;

Zimmerli, Daniel ;

Schneider, Josef ;

Diederich, Francois ;

Kansy, Manfred ;

Mueller, Klaus .

CHEMMEDCHEM, 2007, 2 (08) :1100-1115

[9] Dabuzalgron Hydrochloride.: Treatment of urinary incontinence, α1A/1L-Adrenoceptor partial agonist. [J].

Sorbera, LA ;

Castaner, J .

DRUGS OF THE FUTURE, 2004, 29 (03) :216-219

[10] RHODIUM COMPLEX-CATALYZED DESILYLATIVE CYCLOCARBONYLATION OF 1-ARYL-2-(TRIMETHYLSILYL)ACETYLENES - A NEW ROUTE TO 2,3-DIHYDRO-1H-INDEN-1-ONES [J].

TAKEUCHI, R ;

YASUE, H .

JOURNAL OF ORGANIC CHEMISTRY, 1993, 58 (20) :5386-5392

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