High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.

A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.

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A new and convenient synthesis of the upper-rim monobrominated calix[4]arene Br-calixPR2 is reported and has been used as the key precursor for the preparation of both the diphenyl- (6a) and diisopropylphosphine ligands (6b). Reactions of these new ligands with [(C5Me5)RhCl2]2 afford the complexes (calixPR2)(C5Me5)Rh(Cl)2 (8a,b), which can be converted into their corresponding dihydrides (calixPR2)(C5Me5)Rh(H)2 (9a,b) using NaBH4. 6a also reacts with (C5Me5)Rh(CO)2 to form (calixPPh2)(C5Me5)Rh(CO) (10). The X-ray structures for both 8a and 8b confirm the cone geometry of the calix[4]arene bowl and reveal the presence of the phenyl and isopropyl groups over the cavity. With respect to the Rh−P bond, a gauche conformation is depicted in the solid state. Complexes 8a,b and 9a,b appear to be fluxional in solution, as demonstrated from VT 1H and 31P NMR measurements for 8a,b. Molecular modelings confirm the presence of 13 conformers associated with the rotation around the C(calix)−P and P−Rh bonds and the cavity locking groups above it. The minimum energy conformation for the unsaturated (calixPPh2)(C5Me5)Rh complex exhibits the Rh atom well located at the opening of the free cavity.

[reaction: see text]. A two-step synthesis of N-protected unsaturated amino alcohols is disclosed that relies on an unexpectedly selective cross-metathesis (CM) involving allyl cyanide and pent-4-en-1-ol. The solution concentration and the identity of the Ru complex used are critical to the selectivity and efficiency of CM reactions. The intermediate obtained by CM is converted efficiently to the final desired products through a one-pot nitrile reduction/amine protection procedure.