title: Rapid hit to lead evaluation of pyrazolo[3,4-d]pyrimidin-4-one as selective and orally bioavailable mGluR1 antagonists.
abstract: 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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, AP9A/L16, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL, USA. xueqing.wang@abbott.com
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Teodozyi
authors.initials: T
authors.lastname: Kolasa
authors.forename: Odile F
authors.initials: OF
authors.lastname: El Kouhen
authors.forename: Linda E
authors.initials: LE
authors.lastname: Chovan
authors.forename: Candace L
authors.initials: CL
authors.lastname: Black-Shaefer
authors.forename: Frank L
authors.initials: FL
authors.lastname: Wagenaar
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Garton
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Yau Yi
authors.initials: YY
authors.lastname: Lau
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dandliker
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
mesh_terms: 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*
chemical_list: D011720:Pyrazoles; D011725:Pyridines; D011744:Pyrimidinones; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C447480:pyrazolo(3,4-b)pyridine