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.
Proprotein
convertase subtilisin-like/kexin type 9 (PCSK9) is a
key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated
target for the treatment of hypercholesterolemia and coronary artery
disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely
potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules
such as 44 demonstrated sufficient oral bioavailability
to maintain therapeutic levels in rats and cynomolgus monkeys after
dosing with an enabled formulation. We demonstrated target engagement
and LDL lowering in cynomolgus monkeys essentially identical to those
observed with the clinically approved, parenterally dosed antibodies.
These molecules represent the first report of highly potent and orally
bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles
favorable for potential development as once-daily oral lipid-lowering
agents. In this manuscript, we detail the design criteria and multiparameter
optimization of this novel series of PCSK9 inhibitors.
Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.
Cyclic ethyl 2-diazo-3-hydroxy carboxylates were prepared by treating ethyl diazoacetate with LDA followed by reaction with a series of cyclic ketones. Further treatment of these R-diazo--hydroxy esters with boron trifluoride etherate in various solvents affords an unusual array of products. Product types and ratios were found to be strongly dependent on ring size and the solvent used. The reaction proceeds by Lewis acid complexation of the alcohol functionality of the diazo hydroxy ester with BF 3 etherate followed by neighboring-group participation of the diazo moiety to generate a cycloalkylidene diazonium salt. Loss of nitrogen produces a highly reactive, destabilized, linear vinyl cation. Ring expansion Via a 1,2-methylene shift leads to the formation of a more stable, bent cycloalkenyl vinyl cation. A subsequent 1,2-methylene shift results in ring contraction ultimately leading to a stable allylic cation. This cation is either trapped by the solvent or else undergoes cyclization with the adjacent ester group to give a lactone. Computational studies at the 6-31G* level were performed to determine the geometry of the optimized vinyl cations. Relative energies suggest a moderate energy gain for isomerization of the initial vinyl cation V 1 to the rearranged vinyl cation V 2 followed by a large stabilization in energy for subsequent conversion to the allyl cation A 1 . Compared with isolated product distributions, the energy profiles suggest kinetically-controlled V 1 f V 2 f A 1 migrations. Finally, the calculations suggest that in diethyl ether the carbocations may be coordinated to a molecule of solvent resulting in "protected" cationic intermediates with nonlinear geometries.
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A concise and efficient one-pot synthesis of functionalized sulfonylated pyridines via an S(N)Ar reaction of readily available pyridines and sodium sulfinate salts in the presence of tetrabutylammonium chloride is presented.
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