Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors.

Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.

Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.

Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors.

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.

A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors.

Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aß40-42, compared to their parent compounds.

Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain.

High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.

Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.

An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aß40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aß after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.

Design and synthesis of tricyclic sulfones as gamma-secretase inhibitors with greatly reduced Notch toxicity.

A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.

Discovery of orally efficacious tetracyclic metabotropic glutamate receptor 1 (mGluR1) antagonists for the treatment of chronic pain.

Metabotropic glutamate receptor 1 (mGluR1) plays important roles in the neurotransmission and pathogenesis of several neurological disorders, including chronic pain. Antagonists of mGlur1 are suggested to be useful for the treatment of pain. Herein, we report the discovery of a novel series of tetracyclic mGluR1 antagonists, such as 23c and 23e, with oral efficacy of ED50 of 8 and 5.1 mg/kg, respectively, in rat spinal nerve ligation neuropathic pain model.

Synthesis and structure-activity relationships of piperidine-based melanin-concentrating hormone receptor 1 antagonists.

Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.

Design and synthesis of orally efficacious benzimidazoles as melanin-concentrating hormone receptor 1 antagonists.

Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.

Synthesis and structure-activity relationships of aminoalkylazetidines as ORL1 receptor ligands.

A series of aminoalkylazetidines has been discovered as novel ORL1 receptor ligands. Structure-activity relationships have been investigated at the azetidine N and the alkyl side chain sites. Several potent and selective analogues have been identified.

Synthesis of iodinated biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitors.

The discoveries of Sch 48461 and Sch 58235 and their novel pharmacology of inhibition of cholesterol absorption have prompted efforts to determine their biological mechanism of action (MOA). To this end, a series of radioiodinated analogues with good to excellent in vivo activity have been designed and synthesized as single enantiomers. They are structurally consistent with the allowable SAR of the 2-azetidinone class of cholesterol absorption inhibitors.