Rapid development of two factor IXa inhibitors from hit to lead.
Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA. Electronic address: dann_parker@merck.com.
Dann L
DL
Parker
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Shawn
S
Walsh
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Bing
B
Li
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Esther
E
Kim
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Aurash
A
Sharipour
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Cameron
C
Smith
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Yi-Heng
YH
Chen
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Richard
R
Berger
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Bart
B
Harper
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Ting
T
Zhang
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Min
M
Park
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Min
M
Shu
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Jane
J
Wu
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Jiayi
J
Xu
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Sunita
S
Dewnani
Department of Chemistry Modeling and Informatics, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Edward C
EC
Sherer
Department of Structural Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Alan
A
Hruza
Department of Structural Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Paul
P
Reichert
Department of Pharmacology, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Wayne
W
Geissler
Department of Pharmacology, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Lisa
L
Sonatore
Department of Pharmacology, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Kenneth
K
Ellsworth
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
James
J
Balkovec
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
William
W
Greenlee
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.
Harold B
HB
Wood
D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D055808:Drug Discovery; D015949:Factor IXa / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation
D000925:Anticoagulants; D015949:Factor IXa
Anticoagulant; Factor IXa; Hit-to-lead; Parallel synthesis; Structure based drug design