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Weaver Lab

Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor.

AUTHORS

Bartolomé-Nebreda JMJosé Manuel , Conde-Ceide S Susana , Delgado F Francisca , Iturrino L Laura , Pastor J Joaquín , Pena MÁ Miguel Ángel , Trabanco AA Andrés A , Tresadern G Gary , Wassvik CM Carola M , Stauffer SR Shaun R , Jadhav S Satyawan , Gogi K Kiran , Vinson PN Paige N , Noetzel MJ Meredith J , Days E Emily , Weaver CD C David , Lindsley CW Craig W , Niswender CM Colleen M , Jones CK Carrie K , Conn PJ P Jeffrey , Rombouts F Frederik , Lavreysen H Hilde , Macdonald GJ Gregor J , Mackie C Claire , Steckler T Thomas . Journal of medicinal chemistry. 2013 9 26; 56(18). 7243-59

ABSTRACT

Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.

Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.