Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor.
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
Winters
Michael P
MP
Johnson & Johnson Pharmaceutical Research and Development, 665 Stockton Drive, Exton, PA 19341, USA. mwinter4@prdus.jnj.com
Crysler
Carl
C
Subasinghe
Nalin
N
Ryan
Declan
D
Leong
Lynette
L
Zhao
Shuyuan
S
Donatelli
Robert
R
Yurkow
Edward
E
Mazzulla
Marie
M
Boczon
Lisa
L
Manthey
Carl L
CL
Molloy
Christopher
C
Raymond
Holly
H
Murray
Lynne
L
McAlonan
Laura
L
Tomczuk
Bruce
B
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D001682:Biological Availability; D018893:Bronchoalveolar Lavage; D002264:Carboxylic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D055370:Lung Injury; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry*; D013453:Sulfonylurea Compounds / Q000737:chemistry*
D002264:Carboxylic Acids; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; D013451:Sulfonic Acids; D013453:Sulfonylurea Compounds; D003577:Cytochrome P-450 Enzyme System; C005741:sulfamic acid