Design and synthesis of indane-ureido-thioisobutyric acids: A novel class of PPARalpha agonists.

A series of aminoindane derivatives were synthesized and shown to be potent PPARalpha agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARalpha activation and PPARalpha mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.

Next-generation spirobenzazepines: identification of RWJ-676070 as a balanced vasopressin V1a/V2 receptor antagonist for human clinical studies.

We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.

Indole-glucosides as novel sodium glucose co-transporter 2 (SGLT2) inhibitors. Part 2.

A series of indole-O-glucosides and C-glucosides was synthesized and evaluated in SGLT1 and SGLT2 cell-based functional assays. Compounds 2a and 2o were identified as potent SGLT2 inhibitors and screened in ZDF rats.

Heteroaryl-O-glucosides as novel sodium glucose co-transporter 2 inhibitors. Part 1.

A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.

Synthesis and evaluation of 3-anilino-quinoxalinones as glycogen phosphorylase inhibitors.

A series of 3-anilino-quinoxalinones has been identified as a new class of glycogen phosphorylase inhibitors. The lead compound 1 was identified through high throughput screening as well as through pharmacophore-based electronic screening. Modifications were made to the scaffold of 1 to produce novel analogues, some of which are 25 times more potent than the lead compound.

Glycosylated dihydrochalcones as potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitors.

A series of glucose conjugates was synthesized and tested for inhibition of SGLT1 and SGLT2. The core structure was derived from compound 1a. Modification of the benzofuran moiety and 4'-substituent of the phenyl ring in compound 1a improved selectivity at SGLT2. Select compounds were compared to 1a in metabolic stability and in vivo efficacy studies.

Synthesis and evaluation of nonpeptide substituted spirobenzazepines as potent vasopressin antagonists.

A series of substituted spirobenzazepines was prepared and evaluated as V(1a) and V(2) dual vasopressin receptor antagonists. Compounds 7p and 7q have been shown to be not only potent inhibitors of vasopressin receptors, but also have exhibited an excellent overall pharmaceutical suitability profile.

Benzoxazinones as PPARgamma agonists. 2. SAR of the amide substituent and in vivo results in a type 2 diabetes model.

A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.

2,5-disubstituted 3,4-dihydro-2H-benzo[b][1,4]thiazepines as potent and selective V2 arginine vasopressin receptor antagonists.

A number of 2,5-disubstituted benzothiazepines were synthesized and screened for their ability to inhibit arginine vasopressin binding to the human V(2) and V(1a) receptor subtypes. The more active compounds were subsequently analyzed for their antagonist activity in in vitro functional assays. The SAR showed a preference for an acidic unit appended from the benzothiazepine scaffold. This substitution pattern afforded the most potent and selective analogues in the series. The carboxymethyl analogue 4, showed a 140-fold greater selectivity for the V(2) over the V(1a) receptor in the binding assay. In the cell-based functional assays this analogue was a potent and selective antagonist of the V(2) receptor. The in vitro SAR of the series and a description of the in vivo studies around compound 4 is described.

Hepatic biotransformation of the new calcium-mimetic agent, RWJ-68025, in the rat and in man--API-MS/MS identification of metabolites.

The in-vitro biotransformation of a new calcium-mimetic agent and benzenemethanamine analogue, RWJ-68025, was studied after incubation with rat and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-68025 (44-48% of the sample) plus 12 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS and MS/MS data, and ethyl derivatization for phenolic and carboxylic metabolites. Four metabolic pathways for RWJ-68025 were proposed: pathway 1, O-demethylation; pathway 2, phenyl oxidation; pathway 3, methyl oxidation; and pathway 4, N-dealkylation/acetylation. Pathway 1 formed a major metabolite, O-desmethyl-RWJ-68025 (M1; RWJ-68311; 26% in rat; 16% in human fraction). Pathway 2 produced one major (M2; 12-17% in rat and human fraction) and two minor phenolic metabolites (M4 and M5; all <1% in both species), and in conjunction with step 1, formed hydroxy-M1 (M3; 4-5% in both species). Pathways 3 and 4 formed seven minor oxidized metabolites (M6-M12). RWJ-68025 was extensively metabolized in the rat and human hepatic S9 fractions.

Benzoxazinones as PPARgamma agonists. part 1: SAR of three aromatic regions.

A series of benzoxazinones was synthesized as PPARgamma agonists. The compounds were obtained in seven steps, and SAR was developed by variations to the core shown below. The compounds were tested as functional agonists in the induction of the aP2 gene in preadipocytes, and the most potent compound in the series has an EC(50)=0.51 microM. The potency was further confirmed through a PPAR-Gal4 construct. Efficacy has been demonstrated in the db/db mouse model of hyperglycemia.

Treatment of non-insulin-dependent diabetes mellitus.

Diabetes mellitus has been declared to be at an epidemic level by the World Health Organization. The syndrome is characterised as either Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus. Impaired glucose tolerance for extended periods of time results in serious complications such as kidney damage and impaired blood circulation and is the main cause for blindness and amputations in patients with diabetes. A combination of life-style change, dietary change and oral medications can treat Type II diabetes mellitus effectively and prevent long-term complications. Combination therapy appears to be the most effective approach in controlling blood glucose levels. This review updates the progress made in medicinal chemistry towards promising biological targets, with the development of a new generation of small molecules having improved efficacy and safety profiles.