Rapid hit to lead evaluation of pyrazolo[3,4-d]pyrimidin-4-one as selective and orally bioavailable mGluR1 antagonists.
Our HTS effort yielded a preferential mGluR1 pyrimidinone antagonist 1 with lead-like characteristics. Rapid hit to lead (HTL) study identified compounds with improved functional activity and selectivity such as 1b with little improvements in ADME properties. Addition of an aminosulfonyl group on the N-1 aromatic ring led to 2f, a compound with similar in vitro biochemical profiles as those of 1b but drastically improved in vitro ADME properties. These improvements were paralleled by rat PK study characterized by low clearance and quantitative bioavailability. Compound 2f represented a true lead-like molecule that is amenable for further lead optimization (LO) evaluation.
Wang
Xueqing
X
Neuroscience Research, Global Pharmaceutical Research and Development, AP9A/L16, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL, USA. xueqing.wang@abbott.com
Kolasa
Teodozyi
T
El Kouhen
Odile F
OF
Chovan
Linda E
LE
Black-Shaefer
Candace L
CL
Wagenaar
Frank L
FL
Garton
Jennifer A
JA
Moreland
Robert B
RB
Honore
Prisca
P
Lau
Yau Yi
YY
Dandliker
Peter J
PJ
Brioni
Jorge D
JD
Stewart
Andrew O
AO
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004353:Drug Evaluation, Preclinical; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D011744:Pyrimidinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
D011720:Pyrazoles; D011725:Pyridines; D011744:Pyrimidinones; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C447480:pyrazolo(3,4-b)pyridine