The vasopressin analogue desmopressin (desamino-D-arginine 8 vasopressin, dDAVP, 1) is a potent vasopressin 2 (V 2 ) receptor (V 2 R) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis, and hyponatremia. In search of novel, potent, selective, and short-acting peptidic V 2 R agonists, we synthesized a series of C-terminally truncated analogues of [Val 4 ]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge. The peptides were evaluated for in vitro potency at the human V 2 receptor, selectivity versus the related receptors (human vasopressin 1a receptor, human vasopressin 1b receptor, and human oxytocin receptor), and pharmacokinetic profiles in rodents and other higher species. The truncated analogues show excellent potency at the V 2 R, increased systemic clearance, and shorter half-life in rats. Two compounds 19 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-Agm) and 38 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-D-Arg-NEt 2 ) have been selected for clinical development for nocturia.
A Novel Dieckmann-Type Cyclization, the Final Step of the Synthesis of a Carbacephem Derivative.-Upon treatment with sodium bis(trimethylsilyl)amide followed by triflic anhydride, the azetidinone (I) is cyclized forming the carbacephem derivative (III) as the sole product.-(NEYER, G.; UGI, I.; Synthesis (1991) 9, 743-744; Inst. Org. Chem. Tech. Univ. Muenchen, D-8046 Garching, Fed. Rep. Ger.; EN)
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