Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models.
A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).
Cowart
Marlon D
MD
Department of Neuroscience Research, Abbott Laboratories, Abbott Park, Illinois 60064-6123, USA. marlon.d.cowart@abbott.com
Altenbach
Robert J
RJ
Liu
Huaqing
H
Hsieh
Gin C
GC
Drizin
Irene
I
Milicic
Ivan
I
Miller
Thomas R
TR
Witte
David G
DG
Wishart
Neil
N
Fix-Stenzel
Shannon R
SR
McPherson
Michael J
MJ
Adair
Ronald M
RM
Wetter
Jill M
JM
Bettencourt
Brian M
BM
Marsh
Kennan C
KC
Sullivan
James P
JP
Honore
Prisca
P
Esbenshade
Timothy A
TA
Brioni
Jorge D
JD
D000588:Amines / Q000737:chemistry*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use; D004195:Disease Models, Animal; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use*; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use; D051381:Rats; D011968:Receptors, Histamine / Q000378:metabolism*
D000588:Amines; D000893:Anti-Inflammatory Agents; D006633:Histamine Antagonists; D008024:Ligands; D011743:Pyrimidines; D011968:Receptors, Histamine; C030986:pyrimidine