A series of very potent derivatives of the 30-amino acid peptide hormone glucagon-like peptide-1 (GLP-1) is described. The compounds were all derivatized with fatty acids in order to protract their action by facilitating binding to serum albumin. GLP-1 had a potency (EC(50)) of 55 pM for the cloned human GLP-1 receptor. Many of the compounds had similar or even higher potencies, despite quite large substituents. All compounds derivatized with fatty acids equal to or longer than 12 carbon atoms were very protracted compared to GLP-1 and thus seem suitable for once daily administration to type 2 diabetic patients. A structure-activity relationship was obtained. GLP-1 could be derivatized with linear fatty acids up to the length of 16 carbon atoms, sometimes longer, almost anywhere in the C-terminal part without considerable loss of potency. Derivatization with two fatty acid substituents led to a considerable loss of potency. A structure-activity relationship on derivatization of specific amino acids generally was obtained. It was found that the longer the fatty acid, the more potency was lost. Simultaneous modification of the N-terminus (in order to obtain better metabolic stability) interfered with fatty acid derivatization and led to loss of potency.

We here report a series of derivatives describing the structure-activity relationship around liraglutide, a once-daily human glucagon-like peptide-1 fatty acid derivative, with respect to potency as well as protraction in vivo. The spacer region between the fatty acid and the peptide is mostly important for potency, whereas the fatty acid or fatty acid mimetic is important for both potency and protraction. The length of the fatty acid is the most important parameter for protraction.

Aims The present study had two aims: (i) compare echocardiographic parameters in COVID-19 patients with matched controls and (2) assess the prognostic value of measures of left (LV) and right ventricular (RV) function in relation to COVID-19 related death. Methods and results In this prospective multicentre cohort study, 214 consecutive hospitalized COVID-19 patients underwent an echocardiographic examination (by predetermined research protocol). All participants were successfully matched 1:1 with controls from the general population on age, sex, and hypertension. Mean age of the study sample was 69 years, and 55% were male participants. LV and RV systolic function was significantly reduced in COVID-19 cases as assessed by global longitudinal strain (GLS) (16.4% ± 4.3 vs. 18.5% ± 3.0, P < 0.001), tricuspid annular plane systolic excursion (TAPSE) (2.0 ± 0.4 vs. 2.6 ± 0.5, P < 0.001), and RV strain (19.8 ± 5.9 vs. 24.2 ± 6.5, P = 0.004). All parameters remained significantly reduced after adjusting for important cardiac risk factors. During follow-up (median: 40 days), 25 COVID-19 cases died. In multivariable Cox regression reduced TAPSE [hazard ratio (HR) = 1.18, 95% confidence interval (CI) [1.07-1.31], P = 0.002, per 1 mm decrease], RV strain (HR = 1.64, 95%CI[1.02;2.66], P = 0.043, per 1% decrease) and GLS (HR = 1.20, 95%CI[1.07-1.35], P = 0.002, per 1% decrease) were significantly associated with COVID-19-related death. TAPSE and GLS remained significantly associated with the outcome after restricting the analysis to patients without prevalent heart disease. Conclusions RV and LV function are significantly impaired in hospitalized COVID-19 patients compared with matched controls. Furthermore, reduced TAPSE and GLS are independently associated with COVID-19-related death.

The development and pharmacology of a new potent growth hormone (GH) secretagogue, ipamorelin, is described. Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH 2 ), which displays high GH releasing potency and efficacy in vitro and in vivo. As an outcome of a major chemistry programme, ipamorelin was identified within a series of compounds lacking the central dipeptide Ala-Trp of growth hormone-releasing peptide (GHRP)-1.In vitro, ipamorelin released GH from primary rat pituitary cells with a potency and efficacy similar to GHRP-6 (EC 50 ¼ 1.3Ϯ0.4 nmol/l and E max ¼ 85Ϯ5% vs 2.2Ϯ0.3 nmol/l and 100%). A pharmacological profiling using GHRP and growth hormone-releasing hormone (GHRH) antagonists clearly demonstrated that ipamorelin, like GHRP-6, stimulates GH release via a GHRP-like receptor.In pentobarbital anaesthetised rats, ipamorelin released GH with a potency and efficacy comparable to GHRP-6 (ED 50 ¼ 80Ϯ42 nmol/kg and E max ¼ 1545Ϯ250 ng GH/ml vs 115Ϯ36 nmol/kg and 1167Ϯ120 ng GH/ml).In conscious swine, ipamorelin released GH with an ED 50 ¼ 2.3Ϯ0.03 nmol/kg and an E max ¼ 65Ϯ0.2 ng GH/ml plasma. Again, this was very similar to GHRP-6 (ED 50 ¼ 3.9Ϯ1.4 nmol/kg and E max ¼ 74Ϯ7 ng GH/ml plasma). GHRP-2 displayed higher potency but lower efficacy (ED 50 ¼ 0.6 nmol/kg and E max ¼ 56Ϯ6 ng GH/ml plasma).The specificity for GH release was studied in swine. None of the GH secretagogues tested affected FSH, LH, PRL or TSH plasma levels. Administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol. Very surprisingly, ipamorelin did not release ACTH or cortisol in levels significantly different from those observed following GHRH stimulation. This lack of effect on ACTH and cortisol plasma levels was evident even at doses more than 200-fold higher than the ED 50 for GH release.In conclusion, ipamorelin is the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH. The specificity of ipamorelin makes this compound a very interesting candidate for future clinical development.