2. Academic Validation
  3. Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury

Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury

  • J Med Chem. 2010 Aug 26;53(16):6003-17. doi: 10.1021/jm9013696.
Adrian Huang 1,  Alessandro Moretto,  Kristin Janz,  Michael Lowe,  Patricia W Bedard,  Steve Tam,  Li Di,  Valerie Clerin,  Natalia Sushkova,  Boris Tchernychev,  Desiree H H Tsao,  James C Keith,  Gray D Shaw,  Robert G Schaub,  Qin Wang,  Neelu Kaila
Affiliations

Affiliation

  • 1 Pfizer Global Research and Development, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
PMID: 20718494 DOI: 10.1021/jm9013696
Abstract

Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin Inhibitor. It is active in a variety of animal models of Cardiovascular Disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z