Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known ...as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.
A three-step method was developed to convert N-1 unprotected 3-substituted indoles to 3-substituted 2-acylaminoindoles. Established indole chlorination chemistry was employed to generate stable ...2-trifluoroacetylamino indoles, which were subsequently deprotected and selectively acylated.
Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and ...associated structure–activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
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HCV NS5A inhibitors have demonstrated impressive in vitro virologic profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components ...for inclusion in an all oral fixed-dose combination (FDC) regimen for the treatment of HCV infection. Merck’s effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.
Novel P2X₇ antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X₇ receptor in human and rodent as well as efficacious in rodent pain models. ...Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure–activity relationship (SAR) development and results of pain models are presented.
Structure–activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X₇ receptor antagonists with improved pharmacokinetic profiles. These compounds ...were potent and selective at the P2X₇ receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
Structure–activity relationship (SAR) efforts around our initial lead compound
1 led to the identification of potent P2X
7 receptor antagonists with improved pharmacokinetic profiles. These compounds ...were potent and selective at the P2X
7 receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X sub(7 receptor antagonists with improved pharmacokinetic profiles. These ...compounds were potent and selective at the P2X) sub(7) receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models. AB:
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