Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia

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• 作者：Izzat T. Raheem^a ; ^&dagger ; ; John D. Schreier^a ; ^&dagger ; ; Joy Fuerst^b ; Liza Gantert^c ; Eric D. Hostetler^c ; Sarah Huszar^d ; Aniket Joshi^c ; Monika Kandebo^e ; Somang H. Kim^f ; Jing Li^g ; Bennett Ma^f ; Georgia McGaughey^h ; Sujata Sharmaⁱ ; William D. Shipe^a ; Jason Uslaner^d ; George H. Vandeveer^a ; Youwei Yanⁱ ; John J. Renger^e ; Sean M. Smith^e ; Paul J. Coleman^a ; Christopher D. Cox^a
• 关键词：Schizophrenia ; Antipsychotic activity ; Cognitive improvement ; Phosphodiesterase 10A ; Fragment-based drug discovery ; Pyrazolopyrimidine ; Rational design ; Positron emission tomography
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：26
• 期：1
• 页码：126-132
• 全文大小：2659 K

文摘

Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A K_i = 0.23 nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [¹¹C]MK-8193, a novel PDE10A PET tracer.