Design, synthesis, and biological evaluation of novel somatostatin receptor subtype-2 agonists: Optimization for potency and risk mitigation of hERG and phospholipidosis.

Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD). We investigated the relationship between in silico physicochemical properties and hERG and PLD, and explored well-balanced agonists to identify amide 19 and benzimidazole 30. As a result of this exploration, we found out that the value of (cLogP) [2] + (pKa) [2] needs to be less than 110 to mitigate the liabilities.

Discovery and SAR Studies of Orally Active Somatostatin Receptor Subtype-2 (SSTR2) Agonists for the Treatment of Acromegaly.

Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound (13). Pharmacophore studies enabled scaffold hopping to obtain a unique 3,4,5-trisubstituted pyridine motif. Further optimization conferred potent SSTR2 agonistic activity and metabolic stability. Several compounds were evaluated and these showed good oral pharmacokinetic profiles in rats, and one representative compound (25) showed highly potent inhibition of growth hormone secretion induced by growth hormone-releasing hormone in rats. Based on these results, 25 was identified as a promising lead for further optimization. A structure-activity relationship (SAR) study and the metabolic stability data for this compound are also described.

Synthesis and evaluation of a potent, well-balanced EP2/EP3 dual agonist.

A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.

Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.

The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.

Discovery of novel S1P2 antagonists. Part 2: Improving the profile of a series of 1,3-bis(aryloxy)benzene derivatives.

Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist. This hybridization reaction gave compound 9, which showed improved S1P2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14, which showed potent antagonist activity towards S1P2 with a much smaller species difference between human S1P2 and rat S1P2. Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9.

Discovery of novel S1P2 antagonists. Part 1: discovery of 1,3-bis(aryloxy)benzene derivatives.

The structure-activity relationships of a novel series of sphingosine-1-phosphate receptor antagonists have been examined in detail. The initial hit compound 1 was modified through synthesis to improve its S1P2 activity. The synthesis of a series of analogs revealed that 1,3-bis(aryloxy)benzene derivatives, as represented by 22, are potent and selective S1P2 antagonists.

Discovery of an 8-aza-5-thiaProstaglandin E1 analog as a highly selective EP4 receptor agonist.

For the purpose of discovering an orally available EP4 subtype-selective agonist, a series of 8-aza prostaglandin E(1) (PGE(1)) analogs were synthesized and evaluated for their affinity for PGE(2) receptor subtypes. Additionally, the structure-activity relationships of these compounds were studied. Among the tested compounds, the 8-aza PGE(1) analog 6 and 8-aza-5-thiaPGE(1) analog 12 had highly potent EP4 receptor affinity, good functional activity, and excellent subtype-selectivity. Furthermore, these analogs demonstrated good stability in human liver microsomes. As a result, we concluded that these two series of 8-aza PGE(1) analogs could be promising chemical leads for an orally available EP4 subtype-selective agonist.

Discovery of new orally active prostaglandin D2 receptor antagonists.

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.

Synthesis of phototrappable shape-shifting molecules for adaptive guest binding.

We have designed and synthesized oligosubstituted bullvalenes 1 and 2 as adaptive molecules that can change their shapes in order to bind tightly to a suitable guest. By incorporation of a photolabile o-nitroveratryloxycarbonate (NVOC) group into bullvalenes 1 and 2, tightly binding species can be selectively isolated from a population of hundreds of interconverting structural isomers. Spontaneous strain-assisted Cope rearrangements allow these shape-shifting molecules to exist in a dynamic equilibrium of configurationally distinct valence isomers, as revealed by dynamic NMR and HPLC studies. When NVOC bullvalenes 1 and 2 were exposed to UV light, the cleavage of the NVOC group resulted in a mixture of static isomers of the corresponding bullvalone. Binding studies of NVOC bisporphyrin bullvalene 1 demonstrated that the dynamic isomeric equilibrium shifted in the presence of C(60), favoring configurations with more favorable binding affinities. Irradiation of a mixture of 1 and C(60) with UV light and isolation of the major static isomer yielded an isomer of bisporphyrin bullvalone with a binding affinity for C(60) that was ∼2 times larger than that of the nonadapted isomer bisporphyrin bullvalone 41.

Further optimization of sulfonamide analogs as EP1 receptor antagonists: synthesis and evaluation of bioisosteres for the carboxylic acid group.

4-{[2-[(2-Furylsulfonyl)(isobutyl)amino]-5-(trifluoromethyl)phenoxy]methyl}benzoic acid analogs 2a and b and a series of the acid analogs, in which the carboxylic acid residue of 2b was replaced with various kinds of carboxylic acid bioisosteres, were synthesized and evaluated as EP1 receptor antagonists. Compound 2b and its monocyclic acid analogs, in which the carboxylic acid residue of 2b was replaced with monocyclic acid bioisosteres, were found to show potent EP1 receptor antagonist activity. Optimization of the linker Y between the phenyl moiety and the carboxylic acid residue of 2b was also carried out (Table 5). Compounds 2b and 16 and 17 possessing conformationally restricted linker Y were found to show the most optimized potency among the tested compounds. Cytochrome P450 inhibition of optimized compounds was also investigated. Details of the structure-activity relationship study are presented.

Optimization of sulfonamide derivatives as highly selective EP1 receptor antagonists.

A series of 4-[(2-{isobutyl[(5-methyl-2-furyl)sulfonyl]amino}phenoxy)methyl]benzoic acids and 4-({2-[isobutyl(1,3-thiazol-2-ylsulfonyl)amino]phenoxy}methyl)benzoic acids were synthesized and evaluated for their EP receptor affinities and EP1 receptor antagonist activities. Further structural optimization was carried out to reduce inhibitory activity against hepatic cytochrome P450 isozymes, which could represent a harmful potential drug interaction. Selected compounds were also evaluated for their binding affinities to hTP, hDP, mFP, and hIP, and for their hEP1 receptor antagonist activities. The results of structure-activity relationship studies are also presented.

Discovery of heteroaryl sulfonamides as new EP1 receptor selective antagonists.

4-({2-[Isobutyl(phenylsulfonyl)amino]-5-(trifluoromethyl)phenoxy}methyl)benzoic acid (1) is a functional PGE2 antagonist selective for EP1 receptor subtype. Analogs of 1, in which the phenyl-sulfonyl moiety has been replaced with more hydrophilic heteroarylsulfonyl moieties, exhibited more optimized antagonist activity, while some of them showed in vivo antagonist activity. Structure-activity relationship (SAR) studies are also presented.

Discovery of new chemical leads for selective EP1 receptor antagonists.

A series of 4-([2-[alkyl(phenylsulfonyl)amino]phenoxy]methyl)benzoic acids were identified as functional PGE(2) antagonists with selectivity for the EP1 receptor subtype starting from a chemical lead 1, which was found while screening our in-house compound library. Discovery of the optimized analogs 21-23 is presented here and structure-activity relationships (SAR) are also discussed.

A practical synthesis and biological evaluation of 9-halogenated PGF analogues.

A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.

Development of a highly selective EP2-receptor agonist. Part 2: identification of 16-hydroxy-17,17-trimethylene 9beta-chloro PGF derivatives.

Further chemical modification of 1a and 2 was undertaken to identify a more chemically stable selective EP2-receptor agonist for development as a clinical candidate. 9beta-chloro PG analogues 4a-e and 5a, c-e were found to be potent and selective EP2-receptor agonists. Among them, the compound 4aLy, which is a chemically stabilized lysine salt of 4a, exhibited an excellent profile both in biological activities and physicochemical properties. The agonist 4aLy was found to suppress uterine motility in anesthetized pregnant rats, while PGE2 stimulated uterine motility. Structure-activity relationships (SARs) are discussed.

Development of a highly selective EP2-receptor agonist. Part 1: identification of 16-hydroxy-17,17-trimethylene PGE2 derivatives.

Design and synthesis of an EP2-receptor selective agonist began with the chemical modification of alpha- and omega-chains of butaprost 1a, which exhibits an affinity for the IP-receptor. Two series of prostaglandin (PG) analogues with a 16-hydroxy-17,17-trimethylene moiety as an omega-chain were identified. Among those tested, 4a,b,e,f,h and 6a,b,e,f,h were found to be highly selective EP2-receptor agonists. Structure-activity relationships are discussed.