Mark A. Holmes

A wittig approach to novel C24 and C25-substituted avermectins.

Abstract The Wittig condensation of aldehydes 2A and 2B with the appropriate phosphonium ylids under Bestmanns “salt-free” conditions 3 gave the Z-olefin precursors 3A and 3B respectively. Treatment of 3A and 3B with methanolic pyridinium tosylate effected desilylation and intramolecular spiroketalization to generate synthetic avermectins ( 4 ) having the thermodynamic dioxaspirane configuration found in natural avermectins.

Discovery of highly potent and efficacious MC4R agonists with spiroindane N-Me-1,2,4-triazole privileged structures for the treatment of obesity

We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.

Novel derivatives at the C21 position of the FK-506 macrocycle

Abstract A number of C21 derivatives of FK-506 were prepared and their immunosuppressant properties evaluated in a T-cell proliferation assay. Some of these compounds are surprisingly potent antagonists of FK-506-mediated immunosuppression.

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

A structure-activity relationship study of the imidazolyl-β-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.

An unusual twist in the synthesis and hydrolysis of the 23,24-epoxide of 22,23-dihydroavermectin B1a

Abstract Treatment of 4″,5-di-O-tert-butyldimethylsilyl(or phenoxyacetyl)-7-O-trimethylsilyl-avermectin B 2a ( 1a,b ) with diethylaminosulfur trifluoride (DAST) at 20AC in dichloromethane resulted in net elimination of water to yield 65% of the 23,24-olefin ( 2a,b ), 5–10% 23-fluoroavermectin derivative ( 3a,b ), and 20–25% of two rearranged products ( 4a,b:5a,b in a 2:1 ratio). The trisubstituted 23,24-olefin ( 2a,b ) was selectively epoxidized with m-chloroperbenzoic acid to give a mixture of alpha ( 6a,b major) and beta ( 7a,b minor) 23,24-epoxides in 64% yield. The acid catalyzed hydrolysis of epoxide 6a,b unexpectedly afforded hemiketal 9a,b as the major product (60%) and the usual 23,24-diol 10a,b as the minor product (6%). Subsequent Ley perruthenate oxidation of 9b produced lactone 13b in 15% yield. Lead tetracetate oxidation of 10a produced the desired cleavage product 14a in 40–50% yield.

Disubstituted pyrimidines as Lck inhibitors

We have developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cellular IL2 release.

Synthesis of an avermectin-nemadectin hybrid.

Abstract The Wittig condensation of (2R,3R,4E)-2,6-dimethyl-3-trimethylsilyloxy-4- heptenyltriphenylphosphorylidene with aldehyde 1 produced the desired cis olefin 11 in 45% yield. Treatment of this intermediate with pyridinium tosylate in methanol effected spiroketalization and desilylation with hydrogen fluoride-pyridine in THF afforded the avermectin-nemadectin hybrid 2 .

Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity.

The synthesis of C32-O-arylethyl ether derivatives of ascomycin that possess equivalent immunosuppressant activity but reduced toxicity, compared to FK-506, is described.