Highly potent and selective chiral inhibitors of PDE5: An illustration of Pfeiffer's rule

被引：6

作者：

Bunnage, Mark E. ^{[1
]}

Mathias, John P. ^{[1
]}

Wood, Anthony ^{[1
]}

Miller, Duncan ^{[1
]}

Street, Stephen D. A. ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 23期

关键词：

Pfeiffer's rule; Eudismic analysis; Eudismic; PDE5; inhibitor; Sildenafil; UK-343,664; UK-371,800; Non-linear pharmacokinetics;

D O I：

10.1016/j.bmcl.2008.10.037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of potent chiral PDE5 inhibitors are described that are based on the sildenafil architecture but exhibit much greater selectivity over PDE6. Eudismic analysis of the SAR in this series provided a clear illustration of Pfeiffer's rule and indicated that the chiral motif was involved in a highly-stereoselective interaction with PDE5. This PDE5 specificity translated to levels of selectivity over PDE6 that were hitherto unprecedented in the sildenafil scaffold. UK-371,800 (compound 8) was identified as a development candidate from this series that married sildenafil-like molecular properties with high selectivity over PDE6. Clinical data confirm that UK-371,800 has markedly superior human pharmacokinetics to a previously-described higher molecular weight achiral analogue in this template (compound 1). (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6033 / 6036

页数：4

共 16 条

[1] Potential role for P-glycoprotein in the nonproportional pharmacokinetics of UK-343,664 in man [J].

Abel, S ;

Beaumont, KC ;

Crespi, CL ;

Eve, MD ;

Fox, L ;

Hyland, R ;

Jones, BC ;

Muirhead, GJ ;

Smith, DA ;

Venn, RF ;

Walker, DK .

XENOBIOTICA, 2001, 31 (8-9) :665-676

[2] A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability [J].

Allerton, Charlotte M. N. ;

Barber, Christopher G. ;

Beaumont, Kevin C. ;

Brown, David G. ;

Cole, Susan M. ;

Ellis, David ;

Lane, Charlotte A. L. ;

Maw, Graham N. ;

Mount, Natalie M. ;

Rawson, David J. ;

Robinson, Colin M. ;

Street, Stephen D. A. ;

Summerhill, Nicholas W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (12) :3581-3594

[3]

BUNNAGE MK, 1999, Patent No. 9954333

[4] THE RELEVANCE OF CHIRALITY TO THE STUDY OF BIOLOGICAL-ACTIVITY [J].

CROSSLEY, R .

TETRAHEDRON, 1992, 48 (38) :8155-8178

[5]

Eardley I, 1997, Expert Opin Investig Drugs, V6, P1803, DOI 10.1517/13543784.6.12.1803

[6] Molecular complexity and its impact on the probability of finding leads for drug discovery [J].

Hann, MM ;

Leach, AR ;

Harper, G .

JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES, 2001, 41 (03) :856-864

[7] The influence of drug-like concepts on decision-making in medicinal chemistry [J].

Leeson, Paul D. ;

Springthorpe, Brian .

NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (11) :881-890

[8]

LEHMANN PA, 1978, PROG DRUG RES, V20, P101

[9] Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings [J].

Lipinski, CA ;

Lombardo, F ;

Dominy, BW ;

Feeney, PJ .

ADVANCED DRUG DELIVERY REVIEWS, 1997, 23 (1-3) :3-25

[10]

Maw GN, 1999, ANNU REP MED CHEM, V34, P71

← 1 2 →