Aims To assess the efficacy and safety of one-and two-step dose-increase regimens of lixisenatide once daily in participants with Type 2 diabetes mellitus insufficiently controlled with metformin.Methods This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre study enrolling participants with Type 2 diabetes (n = 484) treated with metformin. Participants were randomized to receive either lixisenatide in a one-step dose increase or a two-step dose increase vs. placebo for 24 weeks, followed by a ≥ 52-week variable double blind period. Primary outcome was HbA 1c reduction at week 24.Results Lixisenatide one-/two-step once daily significantly improved HbA 1c at week 24 compared with placebo (P < 0.0001) and allowed more participants to achieve HbA 1c < 53 mmol/mol (< 7.0%) (P ≤ 0.0005). Improvements were observed in fasting plasma glucose (-0.5/-0.6 vs. +0.1 mmol/l; P < 0.001) and body weight (-2.6/-2.7 vs. -1.6 kg; P < 0.005). At week 24, adverse events were reported by 67.7/70.8/65.6% of participants treated with lixisenatide one-/ two-step/placebo, respectively-nausea and vomiting being reported most frequently. Symptomatic hypoglycaemia occurred in 1.9/2.5% of participants on one-/two-step lixisenatide and 0.6% with placebo, with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable double-blind extension period of at least 52 weeks.Conclusions Lixisenatide one-or two-step dose-increase regimens significantly improved glycaemic control and decreased body weight over 24 weeks and during a long-term extension period without increasing hypoglycaemia. The study confirmed that tolerability in the one-step group was at least similar to the two-step dose increase, with nausea/ vomiting and hypoglycaemia frequency being lower in the one-step regimen.

(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride.

Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.

The formation of a reactive intermediate was found to be responsible for CYP3A4 metabolism-dependent inhibition (MDI) observed with (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenyl-acrylamide (1). Structure-3A4 MDI relationship studies culminated in the discovery of a difluoro analogue, (S)-N-[1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluoro-phenyl)acrylamide (2), as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI.

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC 50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose−response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.