The discovery of sulfonylated dipeptides as potent VLA-4 antagonists.
Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.
Hagmann
W K
WK
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. william_hagmann@merck.com
Durette
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Lanza
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Kevin
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de Laszlo
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Kopka
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Young
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Magriotis
P A
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Li
B
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Lin
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Yang
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Kamenecka
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Chang
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Wilson
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MacCoss
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Mills
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Van Riper
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McCauley
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Egger
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Kidambi
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Lyons
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Vincent
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Stearns
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Colletti
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Teffera
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Tong
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Fenyk-Melody
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Owens
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Levorse
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Kim
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Schmidt
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Mumford
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D000818:Animals; D001682:Biological Availability; D004151:Dipeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry*
D004151:Dipeptides; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D013451:Sulfonic Acids