Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers

W. Howson; WP Armstrong; K. Cassidy; R. Novelli; MA Tchorzewska; A. Jaxa-Chamiec; RE Dolle; TJ Hallam; BK Leigh; JE Merritt; KE Moores; TJ Rink

doi:10.1016/0223-5234(90)90184-5

Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers

W. Howson, WP Armstrong, K. Cassidy, R. Novelli, MA Tchorzewska, A. Jaxa-Chamiec, RE Dolle, TJ Hallam, BK Leigh, JE Merritt, KE Moores, TJ Rink

Center for Drug Discovery

Research output: Contribution to journal › Article › peer-review

Abstract

Receptor mediated calcium entry (RMCE) is a now recognised mechanism by which the influx of Ca²⁺ into cells can occur. Agents which antagonise or block this mechanism are expected to possess anti-platelet aggregation and anti-inflammatory activities. The first series of RMCE blockers based upon the lead compound SC 38249, has been prepared. Their synthesis, activity against ADP evoked Ca²⁺ signals in human platelets and their anti-platelet aggregation activity is described. A trend between the c log P of these compounds and their activity as inhibitors of Ca²⁺ influx into human platelets stimulated by ADP was observed. This SAR study led to a 40-fold increase in activity over the initial lead compound.

Original language	English
Pages (from-to)	595-602
Number of pages	8
Journal	European Journal of Medicinal Chemistry
Volume	25
Issue number	7
DOIs	https://doi.org/10.1016/0223-5234(90)90184-5
State	Published - Sep 1990

Keywords

Ca influx
anti-platelet aggregation
c log P
receptor mediated calcium entry

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10.1016/0223-5234(90)90184-5

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Howson, W., Armstrong, WP., Cassidy, K., Novelli, R., Tchorzewska, MA., Jaxa-Chamiec, A., Dolle, RE., Hallam, TJ., Leigh, BK., Merritt, JE., Moores, KE., & Rink, TJ. (1990). Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers. European Journal of Medicinal Chemistry, 25(7), 595-602. https://doi.org/10.1016/0223-5234(90)90184-5

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title = "Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers",

abstract = "Receptor mediated calcium entry (RMCE) is a now recognised mechanism by which the influx of Ca2+ into cells can occur. Agents which antagonise or block this mechanism are expected to possess anti-platelet aggregation and anti-inflammatory activities. The first series of RMCE blockers based upon the lead compound SC 38249, has been prepared. Their synthesis, activity against ADP evoked Ca2+ signals in human platelets and their anti-platelet aggregation activity is described. A trend between the c log P of these compounds and their activity as inhibitors of Ca2+ influx into human platelets stimulated by ADP was observed. This SAR study led to a 40-fold increase in activity over the initial lead compound.",

keywords = "Ca influx, anti-platelet aggregation, c log P, receptor mediated calcium entry",

author = "W. Howson and WP Armstrong and K. Cassidy and R. Novelli and MA Tchorzewska and A. Jaxa-Chamiec and RE Dolle and TJ Hallam and BK Leigh and JE Merritt and KE Moores and TJ Rink",

year = "1990",

month = sep,

doi = "10.1016/0223-5234(90)90184-5",

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Howson, W, Armstrong, WP, Cassidy, K, Novelli, R, Tchorzewska, MA, Jaxa-Chamiec, A, Dolle, RE, Hallam, TJ, Leigh, BK, Merritt, JE, Moores, KE & Rink, TJ 1990, 'Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers', European Journal of Medicinal Chemistry, vol. 25, no. 7, pp. 595-602. https://doi.org/10.1016/0223-5234(90)90184-5

TY - JOUR

T1 - Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers

AU - Howson, W.

AU - Armstrong, WP

AU - Cassidy, K.

AU - Novelli, R.

AU - Tchorzewska, MA

AU - Jaxa-Chamiec, A.

AU - Dolle, RE

AU - Hallam, TJ

AU - Leigh, BK

AU - Merritt, JE

AU - Moores, KE

AU - Rink, TJ

PY - 1990/9

Y1 - 1990/9

N2 - Receptor mediated calcium entry (RMCE) is a now recognised mechanism by which the influx of Ca2+ into cells can occur. Agents which antagonise or block this mechanism are expected to possess anti-platelet aggregation and anti-inflammatory activities. The first series of RMCE blockers based upon the lead compound SC 38249, has been prepared. Their synthesis, activity against ADP evoked Ca2+ signals in human platelets and their anti-platelet aggregation activity is described. A trend between the c log P of these compounds and their activity as inhibitors of Ca2+ influx into human platelets stimulated by ADP was observed. This SAR study led to a 40-fold increase in activity over the initial lead compound.

AB - Receptor mediated calcium entry (RMCE) is a now recognised mechanism by which the influx of Ca2+ into cells can occur. Agents which antagonise or block this mechanism are expected to possess anti-platelet aggregation and anti-inflammatory activities. The first series of RMCE blockers based upon the lead compound SC 38249, has been prepared. Their synthesis, activity against ADP evoked Ca2+ signals in human platelets and their anti-platelet aggregation activity is described. A trend between the c log P of these compounds and their activity as inhibitors of Ca2+ influx into human platelets stimulated by ADP was observed. This SAR study led to a 40-fold increase in activity over the initial lead compound.

KW - Ca influx

KW - anti-platelet aggregation

KW - c log P

KW - receptor mediated calcium entry

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U2 - 10.1016/0223-5234(90)90184-5

DO - 10.1016/0223-5234(90)90184-5

M3 - Article

AN - SCOPUS:0025122934

SN - 0223-5234

VL - 25

SP - 595

EP - 602

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 7

ER -

Design and synthesis of a series of glycerol-derived receptor mediated calcium entry (RMCE) blockers

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Keywords

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