We report the efficient N-arylation of acyclic secondary amides and
related nucleophiles with aryl nonaflates, triflates, and chlorides. This method
allows for easy variation of the aromatic component in tertiary aryl amides. A
new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was
found to be uniquely effective for this amidation. The critical aspects of the
ligand were explored through synthetic, mechanistic, and computational studies.
Systematic variation of the ligand revealed the importance of (1) a methoxy
group on the aromatic carbon of the “top ring”
ortho to the phosphorus and (2) two highly
electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups.
Computational studies suggest the electron-deficient nature of the ligand is
important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate.
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
[reaction: see text] A synthesis of the C(43)-C(67) fragment of amphidinol 3 (AM3) has been accomplished by a route that features the use of a double allylboration reaction for synthesis of 1,5-diol 4b, which serves as a precursor to dihydropyran 11.
The pyran-containing fragments 1 and 2 of AM3 have been synthesized from the common pyran intermediate 3. Careful orchestration of the alcohol protecting groups was necessary to facilitate deprotection of alcohol functionality in the presence of the chemically sensitive polyene chain.
With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structureguided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.
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